Novel compounds as modulators of gpr-119

ABSTRACT

The present invention relates to novel compounds of formula (A) and (B) as modulators of GPR-119, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of GPR-119 mediated diseases or disorders with them.

This application claims the benefit of Indian Provisional PatentApplication Nos. 1958/CHE/2011 dated 9 Jun. 2011, 2352/CHE/2011 dated 11Jul. 2011, 3462/CHE/2011 dated 7 Oct. 2011, 3463/CHE/2011 dated 7 Oct.2011, 82/CHE/2012 dated 9 Jan. 2012, and US Provisional PatentApplication Nos. 61/543,152 dated 4 Oct. 2011 and 61/543,157 dated 4Oct. 2011, each of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel compounds of formula (A) and (B)as modulators of GPR-119, methods of preparing them, pharmaceuticalcompositions containing them and methods of treatment, prevention and/oramelioration of GPR-119 mediated diseases or disorders with them.

BACKGROUND OF THE INVENTION

Metabolic disorders in general and in particular, obesity and diabetesare the most common human health problems in the developed world. Itsestimated that in developed countries around a third of the populationis at least 20% overweight. In the United States, the percentage ofobese people has increased from 25% at the end of the 1970's, to 33% atthe beginning the 1990's. Obesity is one of the most important riskfactors for NIDDM (noninsulin-dependent diabetes mellitus) which is theresult of an imbalance between caloric intake and energy expenditure,and is highly correlated with insulin resistance and diabetes inexperimental animals and humans.

Obesity is a medical condition in which excess body fat has accumulatedto the extent that it may have an adverse effect on health, leading toreduced life expectancy and/or increased health problems. Body massindex (BMI), a measurement which compares weight and height, definespeople as overweight (pre-obese) if their BMI is between 25 and 30kg/m², and obese when it is greater than 30 kg/m². (see Haslam D W,James W P (2005), “Obesity”, Lancet 366 (9492): 1197-209; World HealthOrganization Obesity pg 6 & 9, 2000). Obesity increases the likelihoodof various diseases, particularly heart disease, type 2 diabetes,breathing difficulties during sleep, certain types of cancer, andosteoarthritis. Obesity is most commonly caused by a combination ofexcessive food energy intake, lack of physical activity, and geneticsusceptibility, although a few cases are caused primarily by genes,endocrine disorders, medications or psychiatric illness. Evidence tosupport the view that some obese people eat little yet gain weight dueto a slow metabolism is limited; on average obese people have a greaterenergy expenditure than their thin counterparts due to the energyrequired to maintain an increased body mass.(http://en.wikipedia.org/wiki/Obesity)

Dieting and physical exercise are the mainstays of treatment forobesity. Moreover, it is important to improve diet quality by reducingthe consumption of energy-dense foods such as those high in fat andsugars, and by increasing the intake of dietary fiber. To supplementthis, or in case of failure, anti-obesity drugs may be taken to reduceappetite or inhibit fat absorption. In severe cases, surgery isperformed or an intragastric balloon is placed to reduce stomach volumeand/or bowel length, leading to earlier satiation and reduced ability toabsorb nutrients from food.

Obesity is a leading preventable cause of death worldwide, withincreasing prevalence in adults and children, and authorities view it asone of the most serious public health problems of the 21st century (seeBarness L A et. al., “Obesity: genetic, molecular, and environmentalaspects”. Am. J. Med. Genet. A 143A (24): 3016-34, 2007). Obesity isstigmatized in much of the modern world (particularly in the Westernworld), though it was widely perceived as a symbol of wealth andfertility at other times in history, the low- and middle income peoplesuffer from obsesity.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight.

Diabetes is one of the major causes of premature illness and deathworldwide. Developing countries are on the radar with huge populationespecially the low- and middle income people being suffering from thesaid disease. The reason being, lack of sufficient diagnosis andtreatment, being made available to the patients. This is reflected fromthe number of deaths attributable to diabetes in 2010 which shows a 5.5%increase over the estimates for the year 2007. Although 80% of type 2diabetes is preventable by changing diet, increasing physical activityand improving the living environment. Yet, without effective preventionand control programmes, the incidence of diabetes is likely to continuerising globally.

Currently it's estimated that 285 million people, corresponding to 6.4%of the worlds adult population, is living with diabetes. The number isexpected to grow to 438 million by 2030, corresponding to 7.8% of theadult population. The largest age group currently affected by diabetesis between 40-59 years. By 2030 this “record” is expected to move to the60-79 age groups with some 196 million cases. With an estimated 50.8million people living with diabetes, India has the world's largestdiabetes population, followed by China with 43.2 million. Unlessaddressed, the mortality and disease burden from diabetes and other NCDswill continue to increase. WHO projects that globally, deaths caused bythese health problems will increase by 17% over the next decade, withthe greatest increase in low- and middle-income countries, mainly in theAfrican (27%) and Eastern Mediterranean (25%) regions. (see: IDF,Diabetes Atlas, 4th edition)

Diabetes is a chronic disease that occurs when the pancreas does notproduce enough insulin, or when the body cannot effectively use theinsulin it produces. Hyperglycemia, or raised blood sugar, is a commoneffect of uncontrolled diabetes and over time leads to serious damage tomany of the body's systems. It implicated in the development of kidneydisease, eye diseases and nervous system problems. Diabetes causes about5% of all deaths globally each year and is likely to increase by >50% inthe next 10 years. Thus the pharmaceutical industry has been on a questto characterize more promising molecular targets to satisfy stringentnew criteria for anti-hyperglycaemic agents.

Type 1 diabetes, also known as insulin-dependent diabetes mellitus(IDDM), is caused by the autoimmune destruction of the insulin producingpancreatic beta-cells, and requires regular administration of exogenousinsulin. Type 1 diabetes usually starts in childhood or young adulthoodmanifesting sudden symptoms of high blood sugar (hyperglycemia).

Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus(NIDDM), manifests with an inability to adequately regulateblood-glucose levels. NIDDM may be characterized by a defect in insulinsecretion or by insulin resistance. NIDDM is a genetically heterogeneousdisease caused by various reasons such as genetic susceptibility toother environmental factors contributing to NIDDM, such as obesity,sedentary lifestyle, smoking, and certain drugs. NIDDM is a chronicdisease resulting from defects in both insulin secretion andsensitivity. In NIDDM patients, the gradual loss of pancreatic β-cellfunction is a characteristic feature of disease progression that isassociated with sustained hyperglycemia and poor outcome. Strategies forpromoting normoglycemia have focused on enhancing glucose stimulatedinsulin secretion (GSIS) through the targeting of G protein-coupledreceptors (GPCRs), such as the glucagon-like peptidel (GLP-1) receptor,which have been shown to mediate this effect. In clinical therapy forNIDDM, metformin, α-glucosidase inhibitors, thiazolidines (TZDs), andsulfonylurea (SU) derivatives (SUs) are widely used as hypoglycaemicagents; however, the side effects of these compounds includehypoglycaemic episodes, weight-gain, gastrointestianal problems, andloss of therapy responsiveness.

Along with GLP-1 receptor as a major targets for the treatment ofdiabetes, GPR119 agonists have also been recognised as a major targetsfor the treatment of diabetes was discussed recently at the AmericanChemical Society 239^(th) National Meeting (2010, San Francisco).

Further glucagon-like peptide 1 receptor agonists have shown promisingtherapeutic benefit over the existing therapy by way of body weight lossin type 2 diabetics, however these being injectables (Exenatide,marketed as Byetta) lack patient compliance there by limiting theirusage. Other glucagon-like peptide 1 receptor agonists such asLiraglutide (Victoza), Albiglutide and Taspoglutide are alsoinjectables.

GPR119 agonists have potential to achieve blood glucose control togetherwith body weight loss in type 2 diabetics, similar to that ofglucagon-like peptide 1 receptor agonists by way of oral route.Accordingly, oral GPR119 agonist would prove to a preferred choice ofdrug therapy for diabetics.

GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressedprimarily in the human pancreas and gastrointestinal tract, hasattracted considerable interest as a drug target for NIDDM. Theactivation of GPR119 increases the intracellular accumulation of cAMP,leading to enhanced glucose-dependent insulin secretion and increasedlevels of the incretion hormones GLP-1 (glucagon-like peptide 1) and GIP(glucose-dependent insulinotropic peptide). (Overton H A et al. CellMetab, 2006, 3, 167-175). In rodent models, orally availableGPR119-specific agonists have been shown to attenuate blood glucoselevels with a simultaneous body weight loss. (Shah U. see Curr Opin DrugDiscov Devel. 2009 July; 12(4):519-32.).

In various animal models of type 2 diabetes and obesity, orallyavailable, potent, selective, synthetic GPR119 agonists: i) lowers bloodglucose without hypoglycaemia; ii) slow diabetes progression; and iii)reduce food intake and body weight.

GPR119 was first described by Fredriksson et al. (see Fredriksson R, et.al. FEBS Lett. 2003; 554:381-388) as a class 1 (rhodopsin-type) orphanG-protein-coupled receptor having no close primary sequence relative inthe human genome. Independently, GPR119 has been studied and describedin the literature under various synonyms including SNORF25 (see: Boniniet al., U.S. Pat. No. 6,221,660, U.S. Pat. No. 6,468,756), RUP3 (Joneset al., WO 2004/065380.), GPCR2 (Takeda et al., FEBS Lett. 2002;520:97-101 2002), 19AJ (see Davey et. al., Expert Opin Ther Targets.2004; 8:165-170.2004), OSGPR116 (see. U.S. Pat. No. 7,083,933) andglucose-dependent insulinotropic receptor (Chu et al., KeystoneSymposium. Diabetes: Molecular Genetics, Signalling Pathways andIntegrated Physiology, Keystone, Colo., USA, 14-19 Jan. 2007, abstract117 and abstract 230).

Early signs of GPR119 as an attractive target were established by theteachings of Hilary Overton and colleagues from (OSI) Prosidion, whofound that the naturally occurring lipid-signalling agentoleoylethanolamide, was capable of reducing the food intake and weightgain in rats, and can exert its effects through the G protein-coupledreceptor (GPCR) GPR119. Found predominantly in the pancreas anddigestive tract in humans and mice, as well as in the rodent brain, themysterious/unknown function of GPR119 was solved.

The demonstration that GPR119 agonists stimulate the release of GLP-1lends further credence to these agents having an effect on body weight,since GLP-1 is known to cause gastric deceleration and increase satiety,phenomena that lead to reduced caloric intake and weight loss in bothanimal models and human subjects (Meier et al., Eur J Pharmacol.;440:269-279, 2002; Zander et al., 2002; Lancet.; 359:824-830. 2002 andNielsen L L Drug Discov Today. 10,703-710, 2005). Possibly as a resultof their effects on GLP-1 secretion, selective small-molecule GPR119agonists inhibit gastric emptying and suppress food intake upon acutedosing to rats, with no indication of drug-induced malaise orconditioned taste aversion (Fyfe et al., Diabetes. 55 Suppl 1:346-P,2006; Diabetes; 56 Suppl 1:532-P, 2007; Overton et. al., Cell Metab.3,167-175, 2006). The hypophagic actions of GPR119 agonists lead toreduced weight gain, fat pad masses and plasma leptin/triglyceridelevels when administered sub-chronically in rodent models of obesity(Fyfe et al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes; 56 Suppl1:532-P, 2007; Overton et. al., Cell Metab. 3,167-175, 2006). Thetesting of potent, selective agonists for food intake and body weighteffects in GPR119-deficient mouse models has not been reported so far.

There are suggesting evidence about the isoforms of GPR119 beenidentified in a number of mammalian species, including rats, mice,hamsters, chimpanzees, rhesus monkeys, cattle and dogs. For example see.Fredriksson et al. FEBS Lett.; 554:381-388,2003; U.S. Pat. No.6,221,660; U.S. Pat. No. 6,468,756 and EP 1338651-A1.

GPR 119 is thus an attractive target from a clinical perspective mainlybecause of GPR119 agonists are capable of lowering blood glucose withouthypoglycaemia; slowing of diabetes progression; and most improtantalyhelping in reduction of food intake and body weight.

More recently Unmesh shah et. al., in Chapter-16 Vitamins & Harmones,Volume 84, pg 415-448 (2010), and Chapter-7. Annual reports in Med Chem44 pg 149-170 (2009) have provided additional insight about GRP119

Patent literature belonging to some of these applicants include thefollowing patents and/or patent applications: WO2011005929A1,WO2009126245A1, WO2008005576A1, WO2008005569A2, WO2007120702A2,WO2007120689A2, WO2007035355A2, WO06127595A1, WO06083491A2,WO06076455A2, WO2006 076243A1, WO05121121A2, WO05007658A2, WO05007647A1,WO04076413A2, WO2004065380; WO2010009183A1, WO2009012277A1,WO2008137436A1, WO2008 137435A1; WO2011041154A1, WO2010008739A2,WO2009014910A2, WO2009 123992A1, WO2008083238A2; WO2010103335A1,WO2010103334A1, WO2010 103333A1, WO2010004348A1, WO2010004347A1,WO2010001166A1, WO2009 050523A1, WO2009050522A1, WO2009034388A1,WO2008081208A1, WO2008081207 A1, WO2008081206A1, WO2008081205A1,WO2008081204A1, WO2007116230A1, WO2007116229A1, WO2007003964A1,WO2007003962A2, WO2007003961A2, WO2007 003960A1, WO05061489A1;WO2011061679A1, WO2011036576A1, WO2010 140092A1, WO2010128425A1,WO2010128414A1, WO2010106457A2; WO2011 062889A1, WO2011 062885A1,WO2011053688A1, WO2010114958A1, WO2010 114957A1, WO2010 075273A1,WO2010075271A1, WO2010075269A1, WO2010 009208A1, WO2010 009207A1,WO2010009195A1, WO2009143049A1, WO2009 055331A2, WO2008 130615A1,WO2008130584A1, WO2008130581A1, WO2008033465A1, WO2008 033464A2,WO2008033460A2, WO2008033456A1, WO2008033431A1, WO2011030139A1,WO2011019538A1, WO2011014520A2, WO2011008663A1, WO2011044001A1,WO2011055770A1, WO2011066137A1, WO2011078306A1, WO2011093501A1,WO2011127051A1, WO2011127106A1, WO2011128394A1, WO2011128395A1,WO2011138427A2, WO2011140160A1, WO2011140161A1, WO2011147951A1,WO2011159657A1, WO2011146335A1, WO2011145718A1, WO2011148922A1,WO2012006955A1, WO2012011707A2, WO2012025811A1, WO2012037393A1,WO2012040279A1, WO2012046249A1, WO2012045363A1, WO2012066077A1,WO2012069948A1, WO2012069917A1.

Further review and literature disclosure on GPR119 molecules have beengiven by Sempl, G et al., (See; Bio org. Med. Chem. Lett. (2011), doi:10.1016/j. bmcl. 2011.03.007), Szewczyk, J. W. Et al., (See; Bio org.Med. Chem. Lett. (2011), doi:10.1016/j.bmcl. 2010.12.086), VincentMascitti et al., (See; Bioorganic & Medicinal Chemistry Letters 21(2011) 1306-1309), Shigeru Yoshida et al., (See; Biochemical andBiophysical Research Communications 400 (2010) 745-751), Yulin Wu et.al., (See; Bioorganic & Medicinal Chemistry Letters 20 (2010)2577-2581), Chu et al., (See; Endocrinology 2008 149:2038-2047), Y Ninget al., (see; British Journal of Pharmacology (2008) 155, 1056-1065), HAOverton et al., (See; British Journal of Pharmacology (2008)153,S76-S81), Carolyn Root et al., (See; Journal of Lipid Research, Volume43, 2002, Pg 1320-1330). All of these patents and/or patent applicationsand literature disclosures are incorporated herein as reference in theirentirety for all purposes.

Despite the advances made in the treatment of metabolic disorders and inparticular in the treatment of diabetes and obesity, challenges remainin terms of the complexities of the diseases involved, and mostimportantly the safety concerns expected from any treatment.Accordingly, there is a need in the art for additional GPR 119modulators with improved efficacy and safety profiles. The compounds,compositions, and pharmaceutical methods provided herein are aimed atmeeting these needs.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds useful as GPR-119modulators and in particular GPR-119 agonists.

In one embodiment, the compound of the present invention has the formula(A) and (B)

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinAr is selected from substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or Cy¹;L₁ is absent or is selected from NR^(a), O, S(O)_(q) or CR^(a)R^(b);L₂ is absent or is selected from NR^(a), O, S(O)_(q) or CR^(a)R^(b);X¹ is CR¹ or N; X² is CR² or N; X³ is CR³ or N and X⁴ is CR⁴ or N;

X is CR or N; Z is NR, CO, O or S(O)_(q);

Cy is selected from substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclic group;Cy¹ is selected from substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclic group;each occurrence of R, R¹, R², R³ and R⁴ may be same or different and isindependently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl,—OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), C(═Y)—R^(a),—CR^(a)R^(b)—C(═Y)—R^(a), —CR^(a)R^(b)—Y—CR^(a)R^(b)—,—C(═Y)—NR^(a)R^(b)—, —NR^(a)R^(b)—C(═Y)—NR^(a)R^(b)—,—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)R^(b)—S(═O)_(q)—NR^(a)R^(b)—,—NR^(a)R^(b)—NR^(a)R^(b)—;each occurrence of R^(a) and R^(b) may be same or different and areindependently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl, orwhen two R^(a) and/or R^(b) substituents are directly bound to a commonatom, they may be joined to form (i) an oxo (═O), thio (═S) or imino(═NR^(d)), or (ii) a substituted or unsubstituted, saturated orunsaturated 3-10 member ring, which may optionally include one or moreheteroatoms which may be same or different and are selected from O,NR^(c) or S;each occurrence of R^(c) is independently selected from hydrogen, nitro,hydroxy, cyano, halogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substitutedor unsubstituted C₃₋₆ cycloalkylalkyl, and substituted or unsubstitutedC₃₋₆ cycloalkenyl;each occurrence of R^(d) is independently hydrogen, hydroxy, halogen,carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocycicyalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, and —ONO₂;each occurrence of Y is independently selected from O, S, and NR^(a);andeach occurrence of q independently represents 0, 1 or 2.

Another embodiment is a compound of the formula (A-I), (A-II), (A-III),(A-IV), (B-I), (B-II), (B-III) or (B-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinZ is NR, CO, O or S(O)_(q); wherein R and q is as defined above forcompound of formula (A) or (B);D and E are independently selected from CH or N;R⁵ is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro,oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, —COOR^(a), —C(O)R^(a),—C(S)R^(a), —C(O)NR^(a)R^(b), —C(O)ONR^(a)R^(b), —NR^(a)R^(b),—NR^(a)CONR^(a)R^(b), —N(R^(a))SOR^(b), —N(R^(a))SO₂R^(b),-(═N—N(R^(a))R^(b)), —NR^(a)C(O)OR^(b), —NR^(a)C(O)R^(b)—,—NR^(a)C(S)R^(b)—NR^(a)C(S)NR^(a)R^(b), —SONR^(a)R^(b)—,—SO₂NR^(a)R^(b)—, —OR^(a), —OR^(a)C(O)NR^(a)R^(b), —OR^(a)C(O)OR^(a)—,—OC(O)R^(a), —OC(O)NR^(a)R^(b), —R^(a)NR^(b)C(O)R^(a), —R^(a)OR^(b),—R^(a)C(O)OR^(b), —R^(a)C(O)NR^(a)R^(b), —R^(a)C(O)R^(b),—R^(a)OC(O)R^(b), —SR^(a), —SOR^(a)—SO₂R^(a), and —ONO₂, wherein R^(a)and R^(b) are as defined in formula (A) or (B);each occurrence of R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k) andR^(l) is independently selected from hydrogen, nitro, hydroxy, cyano,halogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₃₋₆ cycloalkylalkyl, and substituted or unsubstitutedC₃₋₆ cycloalkenyl; or any two of R^(e), R^(f), R^(g), R^(h), R^(i),R^(j), R^(k), R^(l) may be joined to form (i) a substituted orunsubstituted, saturated or unsaturated 3-14 membered ring, which mayoptionally include one or more heteroatoms which may be the same ordifferent and are selected from O, NR′ (where R′ is H or alkyl) or S, or(ii) an oxo (═O), thio (═S) or imino (═NR′) (where R′ is H or alkyl);each of r, s, t and u is 0, 1 or 2 with the proviso that r+s+t+u≠0; andand all the other variables are the same as described above for thecompound of formula (A) and (B),with the proviso

1. that for compound of formula (A-III), wherein Z is O or S and X₄ is Nor CR⁴ then Ar cannot be

2. that for compound of formula (A-IV) wherein Z is O or S and X₁ is Nor CR¹ then Ar cannot be

whereinR¹ and R⁴ is as defined above for compound of formula (A)W is S(═O)₂—R₁, S(═O)₂—NR_(1a)R₁, —C(═O)—R₁, —C(═O)—O—R₁,—C(═O)—NR_(1a)R₁, —NR_(1a)—S(═O)₂—R₁, halo, or a 4 to 10-memberedoptionally substituted heteroaryl, which contains 1-4 heteroatomsselected from N, O, and S;R_(1a), at each occurrence, is independently hydrogen or (C₁-C₈)alkyl;andR₁ is optionally substituted (C₁-C₆)-alkyl, optionally substituted(C₂-C₆)-alkenyl, optionally substituted (C₂-C₆)-alkynyl, optionallysubstituted (C₃-C₁₂)-cycloalkyl, optionally substituted (C₆-C₁₀)aryl, a4 to 10-membered optionally substituted heteroaryl, which contains 1-4heteroatoms selected from N, O, and S; or a 4- to 10-memberedheterocyclyl, which contains 1-4 heteroatoms selected from N, O, and S.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Ar is selectedfrom

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Ar is Cy¹.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Cy¹ is selectedfrom

Further preferred is a compound of formula (A) or (B) wherein L₁ isabsent.

Further preferred is a compound of formula (A) or (B) wherein L₂ isabsent.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Z is NH or N—CH₃.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Z is O.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein Z is S.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein X¹ is CR¹ or N,wherein R¹ is H or Halogen.

Further preferred is a compound of formula (A), (A-II), (A-IV), (B),(B-II) or (B-IV) wherein X² is CH.

Further preferred is a compound of formula (A), (A-II), (A-IV), (B),(B-II) or (B-IV) wherein X³ is CH.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein X⁴ is CR⁴ or N,wherein R⁴ is H or Halogen.

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV) wherein X is CR or N,wherein R is H, hydrogen, cyano, halogen, substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted C₃₋₆ cycloalkenyl, —OR^(a), —NR^(a)R^(b) orC(═Y)—R^(a) and R^(a), R^(b), and Y are as defined above for compound offormula (A) or (B);

Further preferred is a compound of formula (A), (A-I), (A-II), (A-III),(A-IV), (B), (B-I), (B-II), (B-III) or (B-IV): wherein Cy is selectedfrom

Yet another embodiment is a compound of formula (A-IA), (A-IIA), (B-IA),(B-IIA), (B-IIIA) or (B-IVA):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, wherein

Ar is

G is independently selected from

R is substituted or unsubstituted alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl or substituted or unsubstituted cycloalkyl.R⁶ is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, —COOR^(a), —C(O)R^(a),—C(S)R^(a), —C(O)NR^(a)R^(b), —C(O)ONR^(a)R^(b), —NR^(a)R^(b),—NR^(a)CONR^(a)R^(b), —N(R^(a))SOR^(b), —N(R^(a))SO₂R^(b),-(═N—N(R^(a))R^(b)), —NR^(a)C(O)OR^(b), —NR^(a)C(O)R^(b)—,—NR^(a)C(S)R^(b)—NR^(a)C(S)NR^(a)R^(b), —SONR^(a)R^(b)—,—SO₂NR^(a)R^(b)—, —OR^(a), —OR^(a)C(O)NR^(a)R^(b), —OR^(a)C(O)OR^(b)—,—OC(O)R^(a), —OC(O)NR^(a)R^(b), —R^(a)NR^(b)C(O)R^(a), —R^(a)OR^(b),—R^(a)C(O)OR^(b), —R^(a)C(O)NR^(a)R^(b), —R^(a)C(O)R^(b),—R^(a)OC(O)R^(b), —SR^(a), —SOR^(a)—SO₂R^(a), and —ONO₂;each occurrence of R^(a) and R^(b) may be same or different and areindependently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl, orwhen two R^(a) and/or R^(b) substituents are directly bound to a commonatom, they may be joined to form (i) an oxo (═O), thio (═S) or imino(═NR^(d)), or (ii) a substituted or unsubstituted, saturated orunsaturated 3-10 member ring, which may optionally include one or moreheteroatoms which may be same or different and are selected from O,NR^(d) or S;each occurrence of R^(d) is independently hydrogen, hydroxy, halogen,carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocycicyalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, and —ONO₂,p is 0, 1, 2, 3 or 4; andall the other variables (X₁-X₄, X, and R⁵) are the same as describedabove for compound of formula (A), (B), (A-I), (B-I), (A-II) or (B-II).

Yet another embodiment is a compound of formula (A-IIIA) and (A-IVA)

wherein the variables Ar, G, R⁶, and p are defined as above with respectto formulas (A-MA) or (A-IVA), and all the other variables (X₁-X₄, X,and R⁵) are the same as described above for compound of formula (A),(B), (A-I), (B-I), (A-II) or (B-II)with the proviso

1. that for compound of formula (A-IIIA), wherein Z is O or S and X₄ isN or CR⁴ then Ar-G cannot be

2. that for compound of formula (A-IVA) wherein Z is O or S and X₁ is Nor CR¹ then Ar-G cannot be

whereinR¹ and R⁴ is as defined above for compound of formula (A)W is S(═O)₂—R₁, S(═O)₂—NR_(1a)R₁, —C(═O)—R₁, —C(═O)—O—R₁,—C(═O)—NR_(1a)R₁, —NR_(1a)—S(═O)₂—R₁, halo, or a 4- to 10-memberedoptionally substituted heteroaryl, which contains 1-4 heteroatomsselected from N, O, and S;R_(1a), at each occurrence, is independently hydrogen or (C₁-C₈)alkyl;R₁ is optionally substituted (C₁-C₆)-alkyl, optionally substituted(C₂-C₆)-alkenyl, optionally substituted (C₂-C₆)-alkynyl, optionallysubstituted (C₃-C₁₂)-cycloalkyl, optionally substituted (C₆-C₁₀)aryl, a4-10-membered optionally substituted heteroaryl, which contains 1-4heteroatoms selected from N, O, and S; or a 4- to 10-memberedheterocyclo, which contains 1-4 heteroatoms selected from N, O, and S;

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein Ar is selectedfrom.

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein G is selectedfrom.

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein X¹ is CR¹ or N,wherein R¹ is H or Halogen.

Further preferred is a compound of formula (A-IIA), (A-IVA), (B-IIA) or(B-IVA) wherein X² is CH.

Further preferred is a compound of formula (A-IA), (A-IIIA), (B-IA) or(B-IIIA) wherein X³ is CH.

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein X⁴ is CR⁴ or N,wherein R¹ is H or Halogen.

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein X is CH or N.

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA) or(A-IVA) (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R⁵ is selected from

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R⁵ is BOC(—C(O)OC(CH₃)₃).

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA) (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R⁵ is—C(O)OCH(CH₃)₂.

Further preferred is a compound of formula (A-IIA) or (B-IIA) wherein X¹is CH or CF.

In one preferred embodiment, X is N.

In one preferred embodiment, X is CH.

In one preferred embodiment, Z is S

In one preferred embodiment, Z is O.

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein p is 0 or 1.

Further preferred is a compound of formula (A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R⁶ is halogen,substituted or unsubstituted alkyl or —OR^(a); wherein R^(a) issubstituted or unsubstituted alkyl.

Further preferred is a compound of formula ((A-IA), (A-IIA), (A-IIIA),(A-IVA), (B-IA), (B-IIA), (B-IIIA) or (B-IVA) wherein R⁶ is —F, —CH₃,—CF₃ or —OCH₃.

Yet another embodiment is a compound of formula (A-IB) and (A-IIB):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, wherein

Z is O or S Ar1-G is

p is 0, 1-7 or 8and all the variables (R⁶, X₁-X₄, X, and R⁵) are the same as describedabove

Yet another embodiment is a compound of formula (A-IIIB) and (A-IVB):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, wherein

Z is O or S Ar1-G is

p is 0, 1-7 or 8and all the variables (R⁶, X₁-X₄, X, and R⁵) are the same as describedabove.

1. that for compound of formula (A-IIIB), wherein Z is O or S and X₄ isN or CR⁴ then Ar1-G cannot be

2. that for compound of formula (A-IVB) wherein Z is O or S and X₁ is Nor CR¹ then Ar1-G cannot be

whereinR¹ and R⁴ is as defined above for compound of formula (A)W is S(═O)₂—R₁, S(═O)₂—NR_(1a)R₁, —C(═O)—R₁, —C(═O)—O—R₁,—C(═O)—NR_(1a)R₁, —NR_(1a)—S(═O)₂—R₁, halo, or a 4 to 10-memberedoptionally substituted heteroaryl, which contains 1-4 heteroatomsselected from N, O, and S;R_(1a), at each occurrence, is independently hydrogen or (C₁-C₈)alkyl;andR₁ is optionally substituted (C₁-C₆)-alkyl, optionally substituted(C₂-C₆)-alkenyl, optionally substituted (C₂-C₆)-alkynyl, optionallysubstituted (C₃-C₁₂)-cycloalkyl, optionally substituted (C₆-C₁₀)aryl, a4 to 10-membered optionally substituted heteroaryl, which contains 1-4heteroatoms selected from N, O, and S; or a 4 to 10-memberedheterocyclo, which contains 1-4 heteroatoms selected from N, O, and S.

Yet another embodiment is a compound of formula (A-V):

or a pharmaceutically acceptable salt thereof, whereinR¹ is hydrogen or F;R⁵ is as defined above;G is selected from —SO₂R^(a), —C(O)R^(a)R^(b), C₁-C₄ alkyl substitutedwith one or more halogens,and a tetrazole of the formula

each occurrence of R⁶ is independently halogen;each occurrence of R^(a) and R^(b) is independently hydrogen orunsubstituted or substituted C₁-C₆ alkyl; andp is 0, 1, 2 or 3.

In one preferred embodiment of the compound of formula (A-V), R⁵ isselected from —COO—R^(a) and —SO₂—R^(a) (wherein R^(a) is anunsubstituted C₁-C₄ alkyl, C₁-C₄ alkyl with one or more halogens, orC₃-C₆ cycloalkyl).

In a preferred embodiment of the compound of formula (A-V), G isselected from —SO₂R^(a) (where R^(a) is an unsubstituted C₁-C₄ alkyl),—C(O)R^(a)R^(b) (where R^(a) and R^(b) are independently selected fromhydrogen and a C₁-C₄ alkyl optionally substituted with one or morehalogen), a C₁-C₂ alkyl substituted with one or more halogens, and atetrazole of the formula above.

Yet another embodiment is a compound of formula (B-V):

or a pharmaceutically acceptable salt thereof, whereinR⁵ is as defined above;G is selected from —SO₂R^(a);each occurrence of R⁶ is independently halogen;each occurrence of R^(a) is independently hydrogen or unsubstituted orsubstituted C₁-C₆ alkyl; andp is 0, 1, 2 or 3.

In one preferred embodiment of the compound of formula (B-V), R⁵ is—COO—R^(a) where R^(a) is an unsubstituted or substituted C₁-C₆ alkyl.More preferably, R^(a) is an unsubstituted C₁-C₆ alkyl, such as anunsubstituted C₁-C₄ alkyl.

In a preferred embodiment of the compound of formula (B-V), G isselected from —SO₂R^(a) where R^(a) is an unsubstituted C₁-C₄ alkyl,such as methyl.

In a preferred embodiment of the compound of formula (B-V), p is 1 andR⁶ is fluorine. More preferably, the fluorine is at a position ortho thebenzo[d]oxazole group.

Representative compounds of the present invention include thosespecified below (including Table 1 and Table 2) and pharmaceuticallyacceptable salts thereof. The present invention should not be construedto be limited to them.

-   1.    2-[1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole:-   2. Tert-butyl    4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate:-   3.    2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole:-   4. Tert-butyl    4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   5. Tert-butyl    4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate:-   6. Tert-butyl    4-{6-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   7. Isopropyl    4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   8. Tert-butyl    4-{7-fluoro-5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   9. Tert-butyl    4-[5-(4-cyanophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   10. Tert-butyl    4-{5-[3-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   11. Tert-butyl    4-{5-[4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   12. Tert-butyl    4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   13. Tert-butyl    4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   14. Isopropyl    4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   15. Tert-butyl    4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   16.    2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazole:-   17. Tert-butyl    4-[5-(4-cyano-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   18. Isopropyl    4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   19. Tert-butyl    4-{5-[3-fluoro-4-(1H-tetrazol-5-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   20. Tert-butyl    4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   21. Tert-butyl    4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   22. Tert-butyl    4-[5-(3-fluoro-4-isopropoxyphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   23. Cyclobutyl    4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   24. Sec-butyl    4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   25. Pentan-3-yl    4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   26.    5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole:-   27. Isopropyl    4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   28. Isopropyl    4-{5-(4-formylphenyl)benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   29. Isopropyl    4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   30. Isopropyl    4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   31. Isopropyl    4-[5-(4-carbamoyl-3-fluorohenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   32.    1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)benzo[d]oxazol-2-yl]piperidin-1-yl}-2-methylpropan-1-one:-   33. Isopropyl    4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   34.    6-{2-[1-(isopropoxycarbonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}nicotinic    acid:-   35.    5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(methylsulfonyl)piperidin-4-yl]benzo[d]oxazole:-   36. Isopropyl    4-[5-(5-carbamoylpyridin-2-yl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   37. Isopropyl    4-[5-(4-carbamoyl-2-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   38. Isopropyl    4-[5-(4-carbamoyl-2-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   39.    2-Fluoro-4-{2-[1-(3-methylbutanoyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide:-   40.    1-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl]piperidin-1-yl}-3-methylbutan-1-one:-   41.    5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(2-methoxyethyl)piperidin-4-yl]benzo[d]oxazole:-   42. Isopropyl    4-{5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   43.    2-Fluoro-4-[2-(1-isobutyrylpiperidin-4-yl)benzo[d]oxazol-5-yl]benzamide:-   44. Isopropyl    4-[6-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate:-   45. Isopropyl    4-{5-[3-fluoro-4-(2-hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   46. Isopropyl    4-{5-[3-fluoro-4-(isopropylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   47. Isopropyl    4-{5-[4-(N-methylsulfamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   48. Isopropyl    4-{5-[6-(methylcarbamoyl)pyridin-3-yl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   49. Isopropyl    4-{5-[3-methyl-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   50. Isopropyl    4-{5-[4-(cyclopropylcarbamoyl)-3-fluorophenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate:-   51.    2-Fluoro-4-{2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide:-   52. Tert-butyl    4-[5-(4-carbamoyl-3-fluorophenyl)benzofuran-2-yl]-5,6-dihydropyridine-1(2H)-carboxylate:-   53.    2-fluoro-4-{2-[1-(propylsulfonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide:-   56. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate;-   57. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}piperidine-1-carboxylate;-   58.    5-[1(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole;-   59. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate;-   60. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate;-   61.    2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole    2,2,2-trifluoro acetate;-   62.    5-[1(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole.-   63. Tert-butyl    4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate:-   64. Isopropyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate:-   65. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate:-   66. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate:-   67. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate:-   68. Tert-butyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate:-   69. Ethyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate:-   70. Tert-butyl    4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate:-   71. Isopropyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate:-   72. Ethyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate:-   73. Ethyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate:-   74. Benzyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate:-   75. Isobutyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate:-   76. Isopropyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}piperidine-1-carboxylate:-   77. Isopropyl    4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate:-   78. Isopropyl    4-(2-p-tolylbenzo[d]oxazol-6-yl)piperidine-1-carboxylate:-   79.    3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]-5,6-dihydropyridin-1(2H)-ylsulfonyl}propan-1-ol:-   80.    3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}propan-1-ol:-   81.    3-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}propan-1-ol:-   82. Tert-butyl    4-[2-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-5-yl]piperidine-1-carboxylate:-   83.    2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]benzo[d]oxazole:-   84. Tert-butyl    4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate-   85. Isopropyl    4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperazine-1-carboxylate:-   86. Tert-butyl    4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate:-   87. Tert-butyl    4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}piperidine-1-carboxylate:

TABLE 1 Example Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

TABLE 2 56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

Yet another embodiment of the present invention is a method for treatinga GPR119 receptor related disorder by administering to a subject in needof such treatment an effective amount of at least one compound of thepresent invention, such as a compound of formula (A), (A-I), (A-II),(A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB), (A-IIB),(A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA),(B-IIA), (B-IIIA), (B-IVA), (B-IB) (B-IIB), (B-IIIB), (B-IVB), or (B-V)as defined above.

Yet another embodiment of the present invention is a method for treatinga GPR119 receptor related disorder by administering to a subject in needof such treatment an effective amount of at least one compound of thepresent invention, such as a compound of formula (A), (A-I), (A-II),(A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB), (A-IIB),(A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA),(B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB), (B-IVB), or (B-V)as defined above, in combination (simultaneously or sequentially) withat least one other therapeutic agent. In a preferred embodiment, theGPR119 receptor related disorder is a metabolic disorder and inparticular the metabolic disorder is diabetes and/or obesity.

More particularly, the compounds of formula (A), (A-I), (A-II), (A-III),(A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB),(A-IVB), (A-V), (B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA),(B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB), (B-IVB), and (B-V) asdefined above can be administered for the treatment, prevention and/oramelioration of GPR119 receptor associated diseases or disordersincluding, but not limited to, diabetes and other metabolic disorders ordiseases.

Yet another embodiment of the present invention pertains to the use of acompound of the present invention, such as a compound of formula (A),(A-I), (A-II), (A-M), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA),(A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III),(B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB),(B-IVB), or (B-V) as defined above, or a composition thereof in themanufacture of a medicament for modulating the activity of a GPR 119receptor.

More particularly, the present invention pertains to the use of acompound of the present invention, such as a compound of formula (A),(A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA),(A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III),(B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB),(B-IVB), or (B-V) as defined above, or a composition thereof in themanufacture of a medicament for agonizing a GPR 119 receptor

The compounds of the present invention, such as the compounds of formula(A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA),(A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III),(B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB), (B-IIIB).(B-IVB), and (B-V) as defined above are useful in the treatment of avariety of metabolic disorders including, but not limited to, diabetesmellitus, type 1 diabetes, type 2 diabetes, inadequate glucosetolerance, impaired glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemi a,hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X,hypertension, pancreatic beta-cell insufficiency, enteroendocrine cellinsufficiency, glucosuria, metabolic acidosis, cataracts, diabeticnephropathy, diabetic neuropathy, peripheral neuropathy, diabeticcoronary artery disease, diabetic cerebrovascular disease, diabeticperipheral vascular disease, diabetic retinopathy, metabolic syndrome, acondition related to diabetes mellitus, myocardial infarction, learningimpairment, memory impairment, a neurodegenerative disorder, a conditionameliorated by increasing a blood GLP-1 level in an individual with aneurodegenerative disorder, excitotoxic brain damage caused by severeepileptic seizures, Alzheimer's disease, Parkinson's disease,Huntington's disease, prion-associated disease, stroke, motor-neurondisease, traumatic brain injury, spinal cord injury, obesity, delayedwound healing, abnormal heart function, myocardial ischemia, low HDL,high LDL, non-cardiac ischemia, vascular restenosis, pancreatitis,neurodegenerative disease, lipid disorders, cognitive impairment anddementia, bone disease, HIV protease associated lipodystrophy andglaucoma.

More particularly, the compounds of the present invention, such as thecompounds of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA),(A-IIA), (A-IIIA), (A-IVA), (A-IB), (A-IIB), (A-IIIB), (A-IVB), (A-V),(B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA),(B-IB) (B-IIB), (B-IIIB), (B-IVB), and (B-V) as defined above can beadministered for the treatment of metabolic-related disorder selectedfrom the group consisting of type 2 diabetes, hyperglycemia,hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulinresistance, type 1 diabetes, idiopathic type 1 diabetes (type Ib),latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes(EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes ofthe young (MODY), malnutrition-related diabetes, gestational diabetes,coronary heart disease, vascular restenosis, restenosis, restenosisafter angioplasty, peripheral vascular disease, claudication,intermittent claudication, cell death associated with myocardialinfarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandiallipemia, conditions of impaired glucose tolerance (IGT), impairedglucose metabolism, conditions of impaired glucose metabolism,conditions of impaired fasting plasma glucose, metabolic acidosis,ketosis, arthritis, obesity, osteoporosis, hypertension, congestiveheart failure, left ventricular hypertrophy, peripheral arterialdisease, diabetic retinopathy, macular degeneration, cataract, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, metabolic syndrome, syndrome X, premenstrual syndrome,angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transientischemic attacks, stroke, erectile dysfunction, skin and connectivetissue disorders, foot ulcerations, ulcerative colitis, endothelialdysfunction, and impaired vascular compliance.

More particularly, the compounds of the present invention, such as thecompounds of formula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA),(A-IIA), (A-IIIA), (A-IVA), (A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V),(B), (B-I), (B-II), (B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA),(B-IB), (B-IIB), (B-IIIB), (B-IVB), and (B-V) as defined above can beadministered for the treatment of type 2 diabetes, hyperglycemia,hyperlipidemia, hypertriglyceridemia, type 1 diabetes, dyslipidemia, andsyndrome X.

The invention further provides a pharmaceutical composition comprisingone or more compounds of the present invention together with apharmaceutically acceptable carrier. The pharmaceutical composition mayfurther comprise one or more of the active ingredients identified above,such as other anti-cancer agents. In one embodiment, the pharmaceuticalcomposition includes a therapeutically effective amount of one or morecompounds of the present invention, such as at least one compound offormula (A), (A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA),(A-IVA), (A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II),(B-III), (B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB), (B-IIB),(B-IIIB), (B-IVB), or (B-V) as defined above.

Yet another embodiment is a method of treating metabolic disorder in asubject in need thereof by administering a therapeutically effectiveamount of a compound of the present invention. For example, thecompounds of the present invention are effective for treating diabetes(e.g., type II diabetes) and/or obesity.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph of blood glucose over time in C57BI/6J mice accordingto the oral glucose tolerance test (Biological Assay Procedure E) beforeand after oral administration of vehicle (control), compound A (Example64 @ 30 mg/kg), or sitagliptin (10 mg/kg @ 10 mg/kg).

FIG. 2 is a graph of blood glucose over time in C57BI/6J mice accordingto the oral glucose tolerance test (Biological Assay Procedure E) beforeand after oral administration of vehicle (control), compound A (Example42 @ 10 mg/kg), or sitagliptin (10 mg/kg @ 10 mg/kg).

DETAILED DESCRIPTION

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. Accordingly, all combinations of uses andmedical indications described herein specifically embraced by thepresent invention just as if each and every subcombination of uses andmedical indications was individually and explicitly recited herein.

As used herein the following definition shall apply unless otherwiseindicated. Further many of the groups defined herein can be optionallysubstituted. The listing of substituents in the definition is exemplaryand is not to be construed to limit the substituents defined elsewherein the specification.

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having, unless otherwise indicated, from one to eightcarbon atoms, and which is attached to the rest of the molecule by asingle bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl),n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

The term substituted or unsubstituted (C₁₋₄)alkyl refers to an alkylgroup as defined above having up to 4 carbon atoms, and the termsubstituted or unsubstituted (C₁₋₆)alkyl refers to an alkyl group asdefined above having up to 6 carbon atoms.

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having, unless otherwise indicated, 2 to about 10 carbonatoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

The term substituted or unsubstituted (C₂₋₆) alkenyl refers to analkenyl group as defined above having up to 6 carbon atoms.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradicals having at least one carbon-carbon triple bond, and having,unless otherwise indicated, in the range of 2 up to 12 carbon atoms(with radicals having in the range of about 2 up to 10 carbon atomspresently being preferred) e.g., ethynyl, propynyl, and butnyl.

The term substituted or unsubstituted (C₂₋₆) alkynyl refers to analkynyl group as defined above having up to 6 carbon atoms.

The term “alkoxy” denotes an alkyl group as defined above attached viaan oxygen linkage to the rest of the molecule. Representative examplesof these groups are OCH₃ and —OC₂H₅. The term “substituted alkoxy”refers to an alkoxy group where the alkyl constituent is substituted(i.e., —O-(substituted alkyl) wherein the term “substituted alkyl” isthe same as defined above for “alkyl”. For example “alkoxy” refers tothe group —O-alkyl, including, unless otherwise indicated, from 1 to 8carbon atoms of a straight, branched, cyclic configuration andcombinations thereof attached to the parent structure through oxygen.Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,and cyclohexyloxy.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of, unless otherwise indicated, 3 to about 12 carbon atoms suchas cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples ofmulticyclic cycloalkyl groups include perhydronapththyl, adamantyl andnorbomyl groups, bridged cyclic groups, and sprirobicyclic groups, e.g.,sprio (4,4) non-2-yl.

The term “C₃₋₈ cycloalkyl” refers to a cycloalkyl group as defined abovehaving up to 8 atoms.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalcontaining, unless otherwise indicated, in the range of 3 up to about 8carbon atoms directly attached to an alkyl group which are then attachedto the main structure at any carbon from alkyl group that results in thecreation of a stable structure such as cyclopropylmethyl,cyclobuyylethyl, and cyclopentylethyl.

The term “C₃₋₆ cycloalkylalkyl” refers to a cycloalkylalkyl group asdefined above having up to 6 atoms.

The term “cycloalkenyl” refers to cyclic ring-containing radicalscontaining, unless otherwise indicated, in the range of 3 up to about 8carbon atoms with at least one carbon-carbon double bond such ascyclopropenyl, cyclobutenyl, and cyclopentenyl. The term“cycloalkenylalkyl” refers to a cycloalkenyl group directly attached toan alkyl group which are then attached to the main structure at anycarbon from alkyl group that results in the creation of a stablestructure

The term “C₃₋₆ cycloalkenyl” refers to a cycloalkenyl group as definedabove having up to 6 atoms.

The term “aryl” refers to aromatic radicals having, unless otherwiseindicated, in the range of 6 up to 20 carbon atoms such as phenyl,naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above. e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a non-aromatic 3 to 15 memberring radical which, consists of carbon atoms and at least one heteroatomselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a mono-, bi-, tri- or tetracyclic ring system, which may includefused, bridged or spiro ring systems, and the nitrogen, phosphorus,carbon, oxygen or sulfur atoms in the heterocyclic ring radical may beoptionally oxidized to various oxidation states. In addition, thenitrogen atom may be optionally quaternized. The heterocyclic ringradical may be attached to the main structure at any heteroatom orcarbon atom that results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedabove. The heterocylcyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to an alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure. Examplesof such heterocycloalkyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl.

The term “heteroaryl” refers to an optionally substituted 5 to 14 memberaromatic ring having one or more heteroatoms selected from N, O, and Sas ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ringsystem. Examples of such “heterocyclic ring” or “heteroaryl” radicalsinclude, but are not limited to, oxazolyl, thiazolyl, imidazolyl,pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl,indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl,isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl,oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure. The term“substituted heteroaryl” also includes ring systems substituted with oneor more oxide (—O—) substituents, such as pyridinyl N-oxides.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedabove directly bonded to an alkyl group. The heteroarylalkyl radical maybe attached to the main structure at any carbon atom from alkyl groupthat results in the creation of a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to an alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “cyclic ring” refers to a cyclic ring containing, unlessotherwise indicated, 3 to 10 carbon atoms.

The term “substituted” unless otherwise specified, refers tosubstitution with any one or any combination of the followingsubstituents and may be the same or different which one or more areselected from the groups such as hydrogen, hydroxy, halogen, carboxyl,cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocycyl, substituted or unsubstituted heterocycicyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, —COOR′, —C(O)R′, —C(S)R′, —C(O)NR′R″, —C(O)ONR′R″,—NR′R″, —NR′CONR′R″, —N(R′)SOR″, —N(R′)SO₂R″, -(═N—N(R′) R″),—NR′C(O)OR″, —NR′R″, —NR′C(O)R″—, —NR′C(S)R″—NR′C(S)NR″R′″, —SONR′R″—,—SO₂NR′R″—, —OR′, —OR′C(O)NR″R′″, —OR′C(O)OR″—, —OC(O)R′, —OC(O)NR′R″,—R′NR″C(O)R′″, —R′OR″, —R′C(O)OR″, —R′C(O)NR″R′″, —R′C(O)R″, —R′OC(O)R″,—SR′, —SOR′, —SO₂R′, —ONO₂ wherein R′, R″ and R′″ in each of the abovegroups can independently be hydrogen, hydrogen, hydroxy, halogen,carboxyl, cyano, nitro, oxo (═O), thio (═S), imino (═NR′), substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substitutedor unsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocycyl, substituted or unsubstituted heterocycicyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheteroarylalkyl, or any two of R′, R″ and R″ may be joined to form asubstituted or unsubstituted saturated or unsaturated 3-10 memberedring, which may optionally include heteroatoms which may be the same ordifferent and are selected from O, NR^(X) or S or form oxo (═O), thio(═S) or imino (═NR′, where R′ is defined above). The substituents in theaforementioned “substituted” groups cannot be further substituted. Forexample, when the substituent on “substituted alkyl” is “substitutedaryl”, the substituent on “substituted aryl” cannot be “substitutedalkenyl”. Substitution or the combinations of substituents envisioned bythis invention are preferably those that result in the formation of astable or chemically feasible compound. The term stable as used hereinrefers to the compounds or the structure that are not substantiallyaltered when subjected to conditions to allow for their isolation,production, detection and preferably their recovery, purification andincorporation into a pharmaceutical composition.

The term “halo”, “halide”, or, alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” refer to haloalkyl and haloalkoxy groups, respectively,in which the halo is fluorine.

The term “protecting group” or “PG” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, -2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, andnitroethyl. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

The term “stereoisomer” refers to compounds, which have identicalchemical composition, but differ with regard to arrangement of the atomsand the groups in space. These include enantiomers, diastereomers,geometrical isomers, atropisomer or conformational isomers.

All the stereoisomers of compounds described herein are within the scopeof this invention. Racemic mixtures are also encompassed within thescope of this invention. Therefore, single stereochemical isomers aswell enantiomeric, diastereoisomeric and geometric (or conformational)mixtures of the present compounds fall within the scope of theinvention.

Certain of the compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically pure forms andintermediate mixtures. For the instance the non-limiting example ofintermediate mixutures include a mixture of isomers in a ratio of 10:90,13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers canbe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

The term “tautomers” refers to compounds, which are characterized byrelatively easy interconversion of isomeric forms in equilibrium. Theseisomers are intended to be covered by this invention. “Tautomers” arestructurally distinct isomers that interconvert by tautomerization.“Tautomerization” is a form of isomerization and includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order, often the interchange of a single bond with anadjacent double bond. Where tautomerization is possible (e.g. insolution), a chemical equilibrium of tautomers can be reached. Anexample of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconversion ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups unlessotherwise specified are halogen atoms and mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

The term “prodrug” refers to a compound, which is an inactive precursorof a compound, converted into its active form in the body by normalmetabolic processes. Prodrug design is discussed generally in Hardma, etal. (Eds.), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion isprovided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol.14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987). To illustrate, prodrugs can be converted into apharmacologically active form through hydrolysis of, for example, anester or amide linkage, thereby introducing or exposing a functionalgroup on the resultant product. The prodrugs can be designed to reactwith an endogenous compound to form a water-soluble conjugate thatfurther enhances the pharmacological properties of the compound, forexample, increased circulatory half-life. Alternatively, prodrugs can bedesigned to undergo covalent modification on a functional group with,for example, glucuronic acid, sulfate, glutathione, amino acids, oracetate. The resulting conjugate can be inactivated and excreted in theurine, or rendered more potent than the parent compound. High molecularweight conjugates also can be excreted into the bile, subjected toenzymatic cleavage, and released back into the circulation, therebyeffectively increasing the biological half-life of the originallyadministered compound.

The term “ester” refers to a compound, which is formed by reactionbetween an acid and an alcohol with elimination of water. An ester canbe represented by the general formula RCOOR′.

These prodrugs and esters are intended to be covered within the scope ofthis invention.

Additionally the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of hydrogen with deuterium or tritium, or thereplacement of a carbon by ^(13C)- or ^(14C)-enriched carbon.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, and thiamine; chiral bases suchas alkylphenylamine, glycinol, and phenyl glycinol; salts of naturalamino acids such as glycine, alanine, valine, leucine, isoleucine,norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, omithine, lysine, arginine, and serine; quaternaryammonium salts of the compounds of invention with alkyl halides, alkylsulphates such as MeI and (Me)₂SO₄; non-natural amino acids such asD-isomers or substituted amino acids; guanidine; and substitutedguanidine wherein the substituents are selected from nitro, amino,alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts andaluminum salts. Salts may include acid addition salts where appropriatewhich are sulphates, nitrates, phosphates, perchlorates, borates,hydrohalides, acetates, tartrates, maleates, citrates, fumarates,succinates, palmoates, methanesulphonates, benzoates, salicylates,benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) includes thoseembodiments, for example, an embodiment of any composition of matter,composition, method, or process, or the like, that “consist of” or“consist essentially of” the described features.

The term “agonist” generally refers to a moiety that interacts andactivates a receptor, such as, the GPR119 receptor and initiates aphysiological or pharmacological response characteristic of thatreceptor. For example, when moieties activate the intracellular responseupon binding to the receptor, or enhance GTP binding to membranes.

The term “contact or contacting” refers to bringing the indicatedmoieties together, whether in an in vitro system or an in vivo system.Thus, “contacting” a GPR 119 receptor with a compound of the inventionincludes the administration of a compound of the present invention to anindividual, preferably a human, having a GPR 119 receptor, as well as,for example, introducing a compound of the invention into a samplecontaining a cellular or more purified preparation containing a GPR 119receptor.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The terms “in need of treatment” and “in need thereof,” when referringto treatment are used interchangeably to refer to a judgment made by acaregiver (e.g. physician, nurse, or nurse practitioner in the case ofhumans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “modulate or modulating” refers to an increase or decrease inthe amount, quality, response or effect of a particular activity,function or molecule.

The term “pharmaceutical composition” refers to a composition comprisingat least one active ingredient, including but not limited to, salts,solvates, and hydrates of compounds of the present inventionm wherebythe composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

Abbreviations, unless otherwise indicated, used herein have theirconventional meaning within the chemical and biological arts.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to an animal so that both agentsand/or their metabolites are present in the animal at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including, but not limited to, diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment,” “treating,” or “ameliorating” are usedinterchangeably. These terms refers to an approach for obtainingbeneficial or desired results including but not limited to therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thesubject, notwithstanding that the subject may still be afflicted withthe underlying disorder. For prophylactic benefit, the compositions maybe administered to a subject at risk of developing a particular disease,or to a subject reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “subject” or “individual” or “subject” is intended to mean anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates and mostpreferably humans. In another embodiment, the individual is a human andin certain embodiments, the human is an infant, child, adolescent oradult. In one embodiment, the individual is at risk for developing aGPR119-related disorder. In one embodiment, the individual is at riskfor developing a metabolic-related disease or disorder. Individuals whoare at risk include, but are not limited to, those with hereditaryhistory of a metabolic-related disease or disorder, or those in a stateof physical health which puts them at risk for a metabolic-relateddisease or disorder. In another embodiment, the individual has beendetermined, by the care-giver or someone acting under the guidance ofthe care-giver, to have a metabolic-related disease or disorder, 11381The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes, but is not limited to, any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, one or more suitablediluents, fillers, salts, disintegrants, binders, lubricants, glidants,wetting agents, controlled release matrices, colorants/flavoring,carriers, excipients, buffers, stabilizers, solubilizers, andcombinations thereof. Except insofar as any conventional media or agentis incompatible with the active ingredient, its use in the therapeuticcompositions of the invention is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

Method of Treatment

In addition to the foregoing beneficial uses for compounds of thepresent invention as disclosed herein, compounds of the invention areuseful in the treatment of additional diseases. Without limitation,these include the following.

The most significant pathologies in type 2 diabetes are impaired insulinsignaling at its target tissues (“insulin resistance”) and failure ofthe insulin-producing cells of the pancreas to secrete an appropriatedegree of insulin in response to a hyperglycemic signal. Currenttherapies to treat the latter include inhibitors of the β-cellATP-sensitive potassium channel to trigger the release of endogenousinsulin stores, or administration of exogenous insulin. Neither of theseachieves accurate normalization of blood glucose levels and both carrythe risk of inducing hypoglycemia. For these reasons, there has beenintense interest in the development of pharmaceuticals that function ina glucose-dependent action, i.e. potentiators of glucose signaling.

Physiological signaling systems which function in this manner arewell-characterized and include the gut peptides GLP1, GIP and PACAP.These hormones act via their cognate G-protein coupled receptor tostimulate the production of cAMP in pancreatic 3-cells. The increasedcAMP does not appear to result in stimulation of insulin release duringthe fasting or preprandial state. However, a series of biochemicaltargets of cAMP signaling, including the ATP-sensitive potassiumchannel, voltage-sensitive potassium channels and the exocytoticmachinery, are modified in such a way that the insulin secretoryresponse to a postprandial glucose stimulus is markedly enhanced.Accordingly, agonists of novel, similarly functioning, β-cell GPCRs,including GPRl 19, would also stimulate the release of endogenousinsulin and consequently promote normoglycemia in type 2 diabetes.

It is also established that increased cAMP, for example as a result ofGLP-1 stimulation, promotes β-cell proliferation, inhibits β-cell deathand thus improves islet mass. This positive effect on β-cell mass isexpected to be beneficial in both type 2 diabetes, where insufficientinsulin is produced, and type 1 diabetes, where β-cells are destroyed byan inappropriate autoimmune response.

Some β-cell GPCRs, including GPRl 19, are also present in thehypothalamus where they modulate hunger, satiety, decrease food intake,controlling or decreasing weight and energy expenditure. Hence, giventheir function within the hypothalamic circuitry, agonists or inverseagonists of these receptors mitigate hunger, promote satiety andtherefore modulate weight.

It is also well-established that metabolic diseases exert a negativeinfluence on other physiological systems. Thus, there is often theco-development of multiple disease states (e.g. type 1 diabetes, type 2diabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in“syndrome X”) or diseases which clearly occur secondary to diabetesmellitus (e.g. kidney disease, peripheral neuropathy). Thus, it isexpected that effective treatment of the diabetic condition will in turnbe of benefit to such interconnected disease states.

In some embodiments of the present invention the metabolic-relateddisorder is selected from type 2 diabetes, hyperglycemia,hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulinresistance, type 1 diabetes, idiopathic type 1 diabetes (type Ib),latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes(EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes ofthe young (MODY), malnutrition-related diabetes, gestational diabetes,cardiovascular disease, coronary heart disease, vascular restenosis,restenosis, restenosis after angioplasty, peripheral vascular disease,claudication, intermittent claudication, cell death associated withmyocardial infarction (e.g. necrosis and apoptosis), dyslipidemia,post-prandial lipemia, conditions of impaired glucose tolerance (IGT),impaired glucose metabolism, conditions of impaired glucose metabolism,conditions of impaired fasting plasma glucose, metabolic acidosis,ketosis, arthritis, obesity, osteoporosis, hypertension, congestiveheart failure, left ventricular hypertrophy, peripheral arterialdisease, diabetic retinopathy, macular degeneration, cataract, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, metabolic syndrome, syndrome X, premenstrual syndrome,angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transientischemic attacks, stroke, erectile dysfunction, skin and connectivetissue disorders, foot ulcerations, ulcerative colitis, endothelialdysfunction, and impaired vascular compliance.

It will be appreciated that the treatment methods of the invention areuseful in the fields of human medicine and veterinary medicine. Thus,the individual to be treated may be a mammal, preferably human, or otheranimals. For veterinary purposes, individuals include but are notlimited to farm animals including cows, sheep, pigs, horses, and goats;companion animals such as dogs and cats; exotic and/or zoo animals;laboratory animals including mice, rats, rabbits, guinea pigs, andhamsters; and poultry such as chickens, turkeys, ducks, and geese.

The invention also relates to a method of treating diabetes in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a compound of the present invention.

In addition, the compounds described herein may be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

Further the compounds described herein may be used for the treatment ofglomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It may be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes are infectious (bacterial, viral or parasiticpathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease,diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barre syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditis, Ostheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis, chagas¹ disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovasculardisease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention.Examples of cardiovascular conditions include, but are not limited to,atherosclerosis, restenosis, vascular occlusion and carotid obstructivedisease.

The invention further provides methods of modulating GPR119 activity bycontacting a GPR119 receptor with an amount of a compound of theinvention sufficient to modulate the activity of the GPR119. Modulatecan be inhibiting or activating GPR119 activity. In some embodiments,the invention provides methods of agonizing GPR119 activity bycontacting a GRP119 receptor with an amount of a compound of theinvention sufficient to activate the activity of the GPR119 receptor. Insome embodiments, the invention provides methods of agonising in asolution by contacting said solution with an amount of a compound of theinvention sufficient to activate the activity of the GPR119 receptor insaid solution. In some embodiments, the invention provides methods ofagonizing GPR119 activity in a cell by contacting said cell with anamount of a compound of the invention sufficient to activate theactivity of GPR119 receptor in said cell. In some embodiments, theinvention provides methods of agonizing GPR119 activity in a tissue bycontacting said tissue with an amount of a compound of the inventionsufficient to activate the activity of GPR119 receptor in said tissue.In some embodiments, the invention provides methods of agonizing GPR119activity in a organism by contacting said organism with an amount of acompound of the invention sufficient to activate the activity of GPR119receptor in said organism. In some embodiments, the invention providesmethods of agonizing

GPR119 activity in a animal by contacting said animal with an amount ofa compound of the invention sufficient to activate the activity ofGPR119 receptor in said animal. In some embodiments, the inventionprovides methods of agonizing GPR119 activity in a mammal by contactingsaid mammal with an amount of a compound of the invention sufficient toactivate the activity of GPR119 receptor in said mammal. In someembodiments, the invention provides methods of agonizing GPR119 activityin a human by contacting said human with an amount of a compound of theinvention sufficient to activate the activity of GPR119 receptor in saidhuman.

Combination Treatment

The present invention also provides methods for combination therapies inwhich is an agent known to modulate other pathways, or other componentsof the same pathway, or even overlapping sets of target enzymes orreceptors are used in combination with a compound of the presentinvention. In one aspect, such therapy includes but is not limited tothe combination of the subject compound with other agents such as knownantidiabetic, anti-obesity agents or any other agents use for thetreatment of metabolic disorders to provide a synergistic or additivetherapeutic effect.

In the context of the present invention, a compound as described hereinor a pharmaceutical composition thereof can be utilized for modulatingthe activity of GPR 119 receptor related diseases, conditions and/ordisorders as described herein. Examples of modulating the activity ofGPRl19 receptor related diseases include the treatment of metabolicrelated disorders. Metabolic related disorders include, but are notlimited to, hyperlipidemia, type 1 diabetes, type 2 diabetes, andconditions associated therewith, such as, but not limited to coronaryheart disease, ischemic stroke, restenosis after angioplasty, peripheralvascular disease, claudication, intermittent claudication, cell deathassociated with myocardial infarction (e.g. necrosis and apoptosis),dyslipidemia, post-prandial lipemia, conditions of impaired glucosetolerance (IGT), conditions of impaired fasting plasma glucose,metabolic acidosis, ketosis, arthritis, obesity, osteoporosis,hypertension, congestive heart failure, left ventricular hypertrophy,peripheral arterial disease, diabetic retinopathy, macular degeneration,cataract, diabetic nephropathy, glomerulosclerosis, chronic renalfailure, diabetic neuropathy, metabolic syndrome, syndrome X,premenstrual syndrome, coronary heart disease, angina pectoris,thrombosis, atherosclerosis, myocardial infarction, transient ischemicattacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia,hyperlipidemia, hypertriglyceridemia, insulin resistance, impairedglucose metabolism, conditions of impaired glucose tolerance, conditionsof impaired fasting plasma glucose, obesity, erectile dysfunction, skinand connective tissue disorders, foot ulcerations, ulcerative colitis,endothelial dysfunction and impaired vascular compliance. In someembodiments, metabolic related disorders include type 1 diabetes, type 2diabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia and syndrome X. Other examples ofmodulating the activity of GPRl 19 receptor related diseases include thetreatment of obesity and/or overweight by decreasing food intake,inducing satiation (i.e., the feeling of fullness), controlling weightgain, decreasing body weight and/or affecting metabolism such that therecipient loses weight and/or maintains weight.

While a compound of the invention can be administered as the sole activepharmaceutical agent (i.e., mono-therapy), the compound can also be usedin combination with one or more pharmaceutical agents (i.e.,combination-therapy) either administered together or separately for thetreatment of the diseases/conditions/disorders described herein.Therefore, another aspect of the present invention includes methods oftreatment of a metabolic related disorder, including a weight relateddisorder, such as obesity, comprising administering to an individual inneed of prophylaxis and/or treatment a therapeutically effective amountof a compound of the present invention in combination with one or moreadditional pharmaceutical agent as described herein.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A)agonists, serotonin and norepinephrine reuptake inhibitors (for example,sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists,dopamine agonists (for example, bromocriptine), melanocyte-stimulatinghormone receptor analogues, cannabinoid 1 receptor antagonists [forexample, SR141716:N-(piperidin-1-yi)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide],melanin concentrating hormone antagonists, leptons (the OB protein),leptin analogues, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y antagonists,thyromimetic agents, dehydroepiandrosterone or an analogue thereof,glucocorticoid receptor agonists or antagonists, orexin receptorantagonists, urocortin binding protein antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neutrotrophic factors (such asAxokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.and Procter & Gamble Company, Cincinnati, Ohio), human agouti-relatedproteins (AGRP), ghrelin receptor antagonists, histamine 3 receptorantagonists or reverse agonists, neuromedin U receptor agonists,noradrenergic anorectic agents (for example, phentermine, mazindol andthe like) and appetite suppressants (for example, bupropion).

Other anti-obesity agents, including the agents set forth infra, arewell known, or will be readily apparent in light of the instantdisclosure, to one of ordinary skill in the art.

It is understood that the scope of combination-therapy of the compoundsof the present invention with other anti-obesity agents, anorecticagents, appetite suppressant and related agents is not limited to thoselisted above, but includes in principle any combination with anypharmaceutical agent or pharmaceutical composition useful for thetreatment of overweight and obese individuals.

It is understood that the scope of combination-therapy of the compoundsof the present invention with other pharmaceutical agents is not limitedto those listed herein, supra or infra, but includes in principle anycombination with any pharmaceutical agent or pharmaceutical compositionuseful for the treatment of diseases, conditions or disorders that arelinked to metabolic related disorders.

Some embodiments of the present invention include methods of treatmentof a disease, disorder, condition or complication thereof as describedherein, comprising administering to an individual in need of suchtreatment a therapeutically effective amount or dose of a compound ofthe present invention in combination with at least one pharmaceuticalagent selected from the group consisting of: sulfonylureas (for example,glyburide, glipizide, glimepiride and other sulfonylureas known in theart), meglitinides (for example, repaglinide, nateglinide and othermeglitinides known in the art), biguanides (for example, biguanidesinclude phenformin, metformin, buformin, and biguanides known in theart), α-glucosidase inhibitors [for example, acarbose,N-(1,3-dihydroxy-2-propyl)valiolamine (generic name; voglibose),miglitol, and α-glucosidase inhibitors known in the art], peroxisomeproliferators-activated receptor-γ (i.e., PPAR-γ) agonists (for example,rosiglitazone, pioglitazone, tesaglitazar, netoglitazone, GW-409544,GW-501516 and PPAR-γ agonists known in the art), insulin, insulinanalogues, HMG-CoA reductase inhibitors (for example, rosuvastatin,pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin,fluvastatin, cerivastatin, rosuvastatin, pitavastatin, BMS's“superstatin”, and HMG-CoA reductase inhibitors known in the art),cholesterol-lowering drugs (for example, fibrates that include:bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate,clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil,nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, andfibrates known in the art; bile acid sequestrants which include:cholestyramine, colestipol and the like; and niacin), antiplateletagents (for example, aspirin and adenosine diphosphate receptorantagonists that include: clopidogrel, ticlopidine and the like),angiotensin-converting enzyme inhibitors (for example, captopril,enalapril, alacepril, delapril; ramipril, lisinopril, imidapril,benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril,trandolapril, and angiotensin converting enzyme inhibitors known in theart), angiotensin II receptor antagonists [for example, losartan (andthe potassium salt form)], angiotensin II receptor antagonists known inthe art, adiponectin, squalene synthesis inhibitors (for example,(S)-α-[bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono potassium salt(BMS-188494) and squalene synthesis inhibitors known in the art), andthe like. In some embodiments, compounds of the present invention andthe pharmaceutical agents are administered separately. In furtherembodiments, compounds of the present invention and the pharmaceuticalagents are administered together.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include, but not limited to, amylinagonists (for example, pramlintide), insulin secretagogues (for example,GLP-I agonists; exendin-4; insulinotropin (NN2211); acyl CoA cholesterolacetyltransferase inhibitors (for example, ezetimibe, eflucimibe, andlike compounds), cholesterol absorption inhibitors (for example,ezetimibe, pamaqueside and like compounds), cholesterol ester transferprotein inhibitors (for example, CP-529414, JTT-705, CETi-I, and likecompounds), microsomal triglyceride transfer protein inhibitors (forexample, implitapide, and like compounds), cholesterol modulators (forexample, NO-1886, and like compounds), bile acid modulators (forexample, GT103-279 and like compounds), insulin signaling pathwaymodulators, like inhibitors of protein tyrosine phosphatases (PTPases),non-small molecule mimetic compounds and inhibitors ofglutamine-fructose-6-phosphate amidotransferase (GFAT), compoundsinfluencing a dysregulated hepatic glucose production, like inhibitorsof glucose-6-phosphatase (GOPase), inhibitors offructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogenphosphorylase (GP), glucagon receptor antagonists and inhibitors ofphosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase(PDHK) inhibitors, insulin sensitivity enhancers, insulin secretionenhancers, inhibitors of gastric emptying, α₂-adrenergic antagonists,retinoid X receptor (PvXR) agonists, and dipeptidyl peptidase-4 (DPP-IV)inhibitors.

In accordance with the present invention, the combination can be used bymixing the respective active components, a compound of the presentinvention and pharmaceutical agent, either all together or independentlywith a physiologically acceptable carrier, excipient, binder, diluent,etc., as described herein above, and administering the mixture ormixtures either orally or non-orally as a pharmaceutical composition.When a compound or a mixture of compounds of the present invention areadministered as a combination therapy with another active compound thetherapeutic agents can be formulated as separate pharmaceuticalcompositions given at the same time or at different times; or thecompound or a mixture of compounds of the present invention and thetherapeutic agent(s) can be formulated together as a single unit dosage.

Further therapeutic agents that can be combined with a subject compoundmay be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the compounds of theinvention will be co-administered with other agents as described above.When used in combination therapy, the compounds described herein may beadministered with the second agent simultaneously or separately. Thisadministration in combination can include simultaneous administration ofthe two agents in the same dosage form, simultaneous administration inseparate dosage forms, and separate administration. That is, a compounddescribed herein and any of the agents described above can be formulatedtogether in the same dosage form and administered simultaneously.Alternatively, a compound of the present invention and any of the agentsdescribed above can be simultaneously administered, wherein both theagents are present in separate formulations. In another alternative, acompound of the present invention can be administered just followed byand any of the agents described above, or vice versa. In the separateadministration protocol, a compound of the present invention and any ofthe agents described above may be administered a few minutes apart, or afew hours apart, or a few days apart.

The methods in accordance with the invention may include administering aGPR 119 agonist with one or more other agents that either enhance theactivity of the agonist or compliment its activity or use in treatment.Such additional factors and/or agents may produce an augmented or evensynergistic effect when administered with a GPR 119 agonist, or minimizeside effects.

The following general methodology described herein provides the mannerand process of making and using the compound of the present inventionand are illustrative rather than limiting. Further modification ofprovided methodology and additionally new methods may also be devised inorder to achieve and serve the purpose of the invention. Accordingly, itshould be understood that there may be other embodiments which fallwithin the spirit and scope of the invention as defined by thespecification hereto.

Representative compounds of the present invention include thosespecified above in Table 1 and pharmaceutically acceptable saltsthereof. The present invention also includes the intermediate compoundsdiscussed in the examples and elsewhere in the specification as well astheir salts. The present invention should not be construed to be limitedto them.

General Method of Preparation of Compounds of the Invention

The compounds of the present invention may be prepared by the followingprocesses. Unless otherwise indicated, the variables (e.g. Z, X, X₁, X₂,X₃, X₄, Cy, L and Ar) when used in the below formulae are to beunderstood to present those groups described above in relation toformula (A) and (B).

Scheme 1:

This scheme provides a method for the preparation of a compound offormula (A) wherein L₂ is absent, NH or O, X is N, Z is NR or O andother variables such as Cy, X₁, X₂, X₃, X₄, and are the same asdescribed above in relation to formula (A). L₂ is shown as L in thescheme below.

A compound of formula (1) wherein Hal represent halogen and Z is NH or Ocan be coupled with a compound of formula (2) in the presence of asuitable poly phosphoric acid at a sufficiently high temperature to givea compound of (3). The compound of formula (3) can then be coupled witha compound of formula Ar—B(OH)₂ in the presence of a catalyst, such asPalladium tetrakis triphenylphosphine, and a suitable base, such aspotassium carbonate, to give the desired compounds of formula (A), i.ewherein L is absent, X is N, Z is O or NR and other variables are thesame as described above in relation to formula (A).

Similarly, the corresponding compound of formula (3) can be coupled witha compound of the formula Ar—NH₂ or Ar—OH in the presence of a suitablebase, such as potassium carbonate, to give the desired compounds offormula (A), wherein L is NH or O, X is N, Z is O or NR and othervariables are the same as described above in relation to formula (A).

Illustration:

Scheme 2:

This scheme provides a method for the preparation of a compound offormula (A-I) wherein L₁ and L₂ are absent, X is N, Z is O, D is CH, Eis N and other variables such as R^(e-1), X₁, X₃ and X₄ are the same asdescribed above in relation to formula (A-I).

A compound of formula (1a) wherein Hal represents halogen can be coupledwith a compound of formula (2a) in the presence of a suitable polyphosphoric acid at a sufficiently high temperature to give a compound offormula (3a). The compound of formula (3a) can then be coupled with acompound of formula R⁵-Lg (where Lg represents a leaving group) in thepresence of a suitable base such as diisoprpyl amine to give a compoundof formula (4). The compound of formula (4) can then be coupled with acompound of formula Ar—B(OH)₂ in the presence of a catalyst, such asPalladium tetrakis triphenylphosphine, and a suitable base, such aspotassium carbonate, to give the desired compounds of formula (A-I),where X is N, Z is O, D is CH, E is N and other variables are the sameas described above in relation to formula (A-I).

Illustration:

Scheme 3:

This scheme provides a method for the preparation of a compound offormula (A-II) wherein L₁ and L₂ are absent, X is N, Z is O, D is CH, Eis N and other variables such as R^(e-1), X₁, X₂ and X₄ are the same asdescribed above in relation to formula (A-II)

A compound of formula (1b) wherein Hal represent halogen and Z is NH orO can be coupled with a compound of formula (2b) in the presence of asuitable poly phosphoric acid at a sufficiently high temperature to givea compound of formula (3b). The compound of formula (3b) can then becoupled with a compound of formula R⁵-Lg (where Lg is a leaving group)in the presence of a suitable base such as diisoprpyl amine to give thecompound of formula (4a). The compound of formula (4a) can then becoupled with a compound of formula Ar—B(OH)₂ in the presence of acatalyst, such as Palladium tetrakis triphenylphosphine, and a suitablebase, such as potassium carbonate, to give the desired compounds offormula (A-II), X is N, Z is O, D is CH, E is N and other variables arethe same as described above in relation to formula (A-II).

Scheme 3A:

This scheme provides a method for the preparation of a compound offormula (A-II) wherein L₁ and L₂ are absent, X is CH, Z is O, D is CH, Eis N and other variables such as R^(e-1), X₁, X₂ and X₄ are the same asdescribed above in relation to formula (A-II).

A compound of formula (1d) can be coupled with a compound of formula(2c) in the presence of catalyst, such as Palladium tetrakistriphenylphosphine, and a suitable base, such as potassium carbonate, togive a compound of (3c). The compound of formula (3c) can then belithiated followed by treatment with triisopropyl borate to give thecompound of formula (4b). The compound of formula (4b) can then becoupled with a compound of formula (4c) to give a compound of formula(5a) which can then be reduced using suitable reducing agent to give thedesired compounds of formula (A-II) wherein X is C, Z is O, D is CH, Eis N and all the other variables are the same as described above inrelation to formula (A-II).

Illustration:

Scheme 4:

This scheme provides a method for the preparation of compound of formula(B) wherein L₁ is absent, NH or O, X is N, Z is NR or O, L₂ is absentand other variables such as Ar, Cy, X₁, X₂, X₃ and X₄ are the same asdescribed above in relation to formula (B).

A compound of formula (1) wherein Hal represent halogen and Z is NH or Ocan be coupled with a compound of formula (5) in the presence of polyphosphoric acid at a sufficiently high temperature to give a compound offormula (6). The compound of formula (6) can then be coupled with acompound of formula Cy-NH₂ or Cy-OH in the presence of a suitable base,such as potassium carbonate, to give the desired compounds of formula(B) wherein L₁ is NH or O, X is N, Z is O or NR and other variables arethe same as described above in relation to formula (B). Alternately, thecompound of formula (6) can be converted to compound of formula (6a)using 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) underSuzuki coupling conditions. The compound of formula (6a) can then becoupled with a compound of formula Cy-Lg (wherein Lg is an leavinggroup) in the presence of a catalyst, such as Palladium tetrakistriphenylphosphine, and a suitable base, such as potassium carbonate, togive the desired compounds of formula (B), i.e wherein L₁ is absent, Xis N, Z is O or NR and other variables are the same as described abovein relation to formula (B).

Illustration:

Scheme 5:

This scheme provides a method for the preparation of a compound offormula (B-I) wherein L₁ and L₂ are absent, X is N, D is CH, E is N, Zis O and other variables such as R^(e-1), X₁, X₃ and X₄ are the same asdescribed above in relation to formula (B-I).

A compound of formula (1b) wherein Hal represents halogen can be coupledwith a compound of formula (5) in the presence of poly phosphoric acidat a sufficiently high temperature to give a compound of formula (6b).The compound of formula (6b) can then be converted to a compound offormula (6c) using Suzuki coupling. The compound of formula (6c) canthen be coupled with a compound of formula (7) (wherein Pg is aprotecting group) using palladium tetrakis triphenylphosphine and asuitable base, such as potassium carbonate, to provide a compound offormula (8). The compound of formula (8) can then be subjected tohydrogenation to give the compound of formula (9). The compound offormula (9) can then be de-protected followed by coupling with acompound of formula R⁵-Lg wherein Lg is a leaving group to give thedesired compounds of formula (B-I).

Illustration:

Scheme 6:

This scheme provides a method for the preparation of a compound offormula (B-II) wherein L₁ and L₂ are absent, X is N, D is CH, E is N, Zis O and other variables such as R^(e-1), X₁, X₂ and X₄ are the same asdescribed above in relation to formula (B-II).

Illustration:

A compound of formula (1c) wherein Hal represents halogen can be coupledwith a compound of formula (5) in the presence of a suitable polyphosphoric acid at sufficiently high temperature to give a compound offormula (6d). The compound of formula (6d) can then be converted tocompound of formula (6e) using Suzuki coupling. The compound of formula(6e) can then be coupled with a compound of formula (7) using palladiumtetrakis triphenylphosphine and a suitable base, such as potassiumcarbonate, to provide a compound of formula (8a). The compound offormula (8a) can then be subjected to hydrogenation to give the compoundof formula (9a). The compound of formula (9a) can then be de-protectedfollowed by coupling with a compound of formula R⁵-Lg wherein Lg is aleaving group to give the desired compounds of formula (B-II).

Similar methodologies with certain modifications as known to thoseskilled in the art can be used to synthesize compounds of formula (A),(A-I), (A-II), (A-III), (A-IV), (A-IA), (A-IIA), (A-IIIA), (A-IVA),(A-IB) (A-IIB), (A-IIIB), (A-IVB), (A-V), (B), (B-I), (B-II), (B-III),(B-IV), (B-IA), (B-IIA), (B-IIIA), (B-IVA), (B-IB) (B-IIB), (B-IIIB),(B-IVB), and (B-V) wherein all the variables are to be understood topresent those groups described above in relation to formula (A) or (B)using suitable intermediates and reagents.

EXPERIMENTAL

Unless otherwise mentioned, work-up refers to distribution of a reactionmixture between the aqueous and organic phases indicated withinparenthesis, separation and drying over Na₂SO₄ of the organic layer andevaporating the solvent to give a residue. Unless otherwise stated,purification refers to column chromatography using silica gel as thestationary phase and a mixture of petroleum ether (boiling at 60-80° C.)and ethyl acetate or dichloromethane and methanol of suitable polarityas the mobile phases. RT generally refers to ambient temperature (25-28°C.).

Intermediates

TABLE 3

Intermediate 1

Intermediate 2

Intermediate 3

Intermediate 4

Intermediate 5

Intermediate 6

Intermediate 7

Intermediate 8

Intermediate 9

Intermediate 10

Intermediate 11

Intermediate 12

Intermediate 13

Intermediate 14

Intermediate 15

Intermediate 16

Intermediate 17

Intermediate 18

Intermediate 19

Intermediate 20

Intermediate 21

Intermediate 22

Intermediate 23

Intermediate 24

Intermediate 25

Intermediate 26

Intermediate 27

Intermediate 28

Intermediate 29

Intermediate 30

Intermediate 31

Intermediate 32

Intermediate 33

Intermediate 34

Intermediate 35

Intermediate 36

Intermediate 37

Intermediate 38

Intermediate 39

Intermediate 40

Intermediate 41

Intermediate 42

Intermediate 43

Intermediate 44

Intermediate 45

Intermediate 46

Intermediate 47

Intermediate 48

Intermediate 49

Intermediate 50

Intermediate 51

Intermediate 52

Intermediate 53

Intermediate 54

Intermediate 55

Intermediate 56

Intermediate 57

Intermediate 58

Intermediate 1: 5-Bromo-2-(piperidin-4-yl)-1H-benzo[d]imidazole

4-bromobenzene-1,2-diamine (1.43 g, 7.64 mmol) andpiperidine-4-carboxylic acid (0.99 g, 7.64 mmol) were dissolved inpolyphosphoric acid (20 g). This mixture was heated at 190° C. for threeand half hours. Reaction mixture cooled to rt and diluted with water(100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 14.Solid was filtered, washed with methanol and dried to obtain the titlecompound (1 g) as a dark brown solid.

Intermediate 2: 5-Bromo-2-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-1H-benzo[d]imidazole

Intermediate 1 (500 mg, 1.69 mmol) and 2-chloro-5-ethylpyrimidine (264mg, 1.86 mmol) were dissolved in propan-2-ol (25 ml). To this mixtureN,N-Diisopropylethyl amine (1.8 ml, 10.1 mmol) added and stirred at 90°C. for 12 h. After completion of the reaction, propan-2-ol was removedto obtain the crude. Crude was purified by combiflash using a mixture ofAcOET and Petether (40:60) as eluent to afford the titled compound (0.2g) as a pale-yellow solid.

Intermediate 3:2-[2-Fluoro-4-(methylsulfonyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-bromo-2-fluoro-4-(methylsulfonyl)benzene (900 mg, 3.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.15 g, 4.5mmol) and potassium acetate (1.13 g, 11.48 mmol) were dissolved indioxane (30 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (85 mg, 0.1 mmol).This mixture stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a mixture of AcOEt and Petether (20:80) to afford thetitled compound (900 mg) as a white solid. ¹H-NMR (δ ppm, CDCl₃, 400MHz): 7.97-7.92 (m, 1H), 7.70 (dd, J 1.4, 7.7, 1H), 7.60 (dd, J 1.2,8.1, 1H), 3.05 (s, 3H), 1.37 (s, 12H).

Intermediate 4: Tert-butyl4-(5-bromo-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate

Intermediate 1 (200 mg, 0.68 mmol) was dissolved in DCM (40 ml) andadded TEA (0.2 ml, 0.68 mmol). Reaction mixture cooled to 0° C. andadded di-tert-butyl dicarbonate (0.2 ml, 0.68 mmol). Reaction mixturestirred at 0° C. for 2 h. After completion of the reaction, reactionmixture washed with water, DCM layer dried over Na₂SO₄ and removal ofDCM afforded the crude. Crude was purified by combiflash using AcOEt andPetether (35:65) as eluent to afford the titled compound (60 mg) as abrown solid.

Intermediate 5: 5-Bromo-2-(piperidin-4-yl)benzo[d]oxazole

2-amino-4-bromophenol (1.2 g, 5.8 mmol) and piperidine-4-carboxylic acid(0.74 g, 5.8 mmol) were dissolved in polyphosphoric acid (30 g). Thismixture was heated at 190° C. for three and half hours. Reaction mixturecooled to rt and diluted with water (100 ml). Aqueous layer basifiedwith sodium hydroxide pellets to pH 9. Work up (AcOEt/H₂O) followedremoval of AcOEt afforded the titled compound (0.8 g) as a pale-yellowgummy solid.

Intermediate 6:5-Bromo-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazole

Intermediate 5 (800 mg, 2.85 mmol) and 2-chloro-5-ethylpyrimidine (447mg, 3.14 mmol) were dissolved in propan-2-ol (25 ml). To this mixtureN,N-Diisopropylethyl amine (3.1 ml, 17.12 mmol) added and stirred at 90°C. for 12 h. After completion of the reaction, propan-2-ol was removedto obtain the crude. Crude was purified by combiflash using a mixture ofAcOEt and Petether (8:92) as eluent to afford the titled compound (80mg) as a pale-yellow solid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.19 (s,2H), 7.81 (s, 1H), 7.41 (dd, J 1.6, 8.6, 1H), 7.35 (d, J 8.6, 1H), 4.72(d, J 13.6, 2H), 3.27-3.11 (m, 3H), 2.47 (q, J 7.6, 2H), 2.21 (dd, J2.6, 13.1, 2H), 2.02-1.90 (m, 2H), 1.19 (t, J 7.6, 3H).

Intermediate 7: Tert-butyl 4-(5-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 5 (500 mg, 1.78 mmol) was dissolved in DCM (30 ml) andadded TEA (180 mg, 1.78 mmol). Reaction mixture cooled to 0° C. andadded di-tert-butyl dicarbonate (388 mg, 1.78 mmol). Reaction mixturestirred at 0° C. for 1 h. After completion of the reaction, reactionmixture washed with water, DCM layer dried over Na₂SO₄ and removal ofDCM afforded the crude. Crude was purified by combiflash using AcOEt andPetether (8:92) as eluent to afford the titled compound (150 mg) as anoff-white solid.

Intermediate 8: tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 7 (1.8 g, 6.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.2 g, 8.6mmol) and potassium acetate (2.1 g, 21.8 mmol) were dissolved in dioxane(20 ml) under N₂ atmosphere. This mixture was degassed with nitrogen for30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (210 mg, 0.26 mmol). Reactionmixture was stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a mixture of AcOEt and Petether (10:90) as eluent toafford the titled compound (1.3 g) as a brown solid.

Intermediate 9: 6-bromo-2-(piperidin-4-yl)benzo[d]oxazole

2-amino-5-bromophenol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg,6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixturewas heated to 190° C. for 3 h. After 3 h, reaction mixture cooled to rtand basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H₂O)followed by removal of EtOAc afforded the title compound (500 mg) as ablack solid. It was used in the next step without further purification.

Intermediate 10: tert-butyl4-(6-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 9 (500 mg, 1.77 mmol) was dissolved in DCM (20 mol), cooledto 0° C. and added TEA (0.25 ml, 1.77 mmol). To this mixture (Boc)₂O(0.4 ml, 1.77 mmol) was added and stirred at rt for 3 h. At this stage,reaction mixture diluted with water and extracted with DCM. DCM removedon rotavapour to obtain the crude. Crude was purified by combiflashusing EtOAc and Petether (7.5%) as eluent to obtain the title compound(500 mg). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.65 (d, J 1.6, 1H), 7.53 (d,J 8.4, 1H), 7.43 (dd, J 1.7, 8.4, 1H), 4.13 (d, J 9.9, 2H), 3.17-3.05(m, 1H), 2.97 (t, J 12.6, 2H), 2.20-2.08 (m, 2H), 1.96-1.82 (m, 2H),1.47 (s, 9H).

Intermediate 11: 5-bromo-7-fluoro-2-(piperidin-4-yl)benzo[d]oxazole

2-amino-4-bromo-6-fluorophenol (1.7 g, 8.24 mmol) and isonipecotic acid(1.06 g, 8.24 mmol) were dissolved in polyphosphoric acid (28 g). Thismixture was heated to 195° C. for 3 h. After 3 h, reaction mixturecooled to rt and basified with aqueous NaOH solution to pH 14. Solidthat obtained was filtered and dried to obtain the title compound (1.3g) as a brown solid.

Intermediate 12: Tert-butyl 4-(5-bromo-7-fluorobenzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 11 (1.3 g, 4.36 mmol) was dissolved in DCM (40 mol), cooledto 0° C. and added TEA (1.2 ml, 8.72 mmol). To this mixture (Boc)₂O (950mg, 4.36 mmol) was added and stirred at rt for 3 h. At this stagereaction mixture diluted with water and extracted with DCM. DCM removedon rotavapour to obtain the crude. Crude was purified by combiflashusing EtOAc and Petether (10:90) as eluent to obtain the title compound(200 mg) as a brick brown solid.

Intermediate 13: Isopropyl4-(5-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 5 (980 mg, 3.31 mmol) was dissolved in DCM (50 mol) andadded TEA (0.45 ml, 3.31 mmol). Reaction mixture cooled to 0° C.,isopropylchloro formate (2.7 ml, 6.62 mmol) was added and stirred thereaction mixture for 3 h at rt. Work up (DCM/H₂O) followed by columnpurification on 60-120 mesh silica gel using EtOAc and Petether (15:85)as eluent afforded the titled compound (500 mg) as a pale-red solid.

Intermediate 14: Isopropyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 7 (0.35 g, 0.95 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.31 g,1.23 mmol) and potassium acetate (0.3 g, 3.14 mmol) were dissolved indioxane (20 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (31 mg, 0.04 mmol).Reaction mixture was stirred at 105° C. for 12 h. Reaction mixturediluted with water and work up (AcOEt/H₂O) afforded the crude. Crude waspurified by combiflash using a gradient mixture of AcOEt and Petether(20:80) as eluent to afford the titled compound (0.3 g) as a pale-redsolid.

Intermediate 15: Isopropyl4-(6-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 9 (1.3 g, 4.4 mmol) was dissolved in DCM (50 mol) and addedTEA (1.22 ml, 8.8 mmol). Reaction mixture cooled to 0° C.,isopropylchloro formate (2.6 ml, 6.6 mmol) was added and stirred thereaction mixture for 3 h at rt. Work up (DCM/H₂O) followed bypurification on combiflash using gradient mixture of EtOAc and Petether(15:85) as eluent afforded the titled compound (510 mg) as a brownviscous liquid.

Intermediate 16: Isopropyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate

Intermediate 15 (0.51 g, 1.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.45 g, 1.8mmol) and potassium acetate (0.4 g, 4.2 mmol) were dissolved in dioxane(20 ml) under N₂ atmosphere. This mixture was degassed with nitrogen for30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (45 mg, 0.05 mmol). Reactionmixture was stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a gradient mixture of AcOEt and Petether (15:85) aseluent to afford the titled compound (0.36 g) as a brown viscous liquid.

Intermediate 17: 5-(4-bromo-2-fluorophenyl)-1H-tetrazole

2-Fluoro-4-bromobenzonitrile (300 mg, 1.5 mmol) dissolved in EtOH, addedsodium azide (320 mg, 4.9 mmol), Zinc chloride (240 mg, 1.8 mmol). Thismixture was stirred refluxed for 38 h. Work up (EtOAc/H₂O) afforded thecrude. Crude was washed with petether to obtain the titled compound (120mg) as a white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.89-7.79 (m,1H), 7.59 (dd, J 1.6, 10.04, 1H), 7.45 (dd, J 1.8, 8.3, 1H).

Intermediate 18:5-Bromo-2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazole

Intermediate 5 (1 g, 3.4 mmol) and 2-Chloro-5-fluoropyrimidine wasdissolved in isopropanol (20 ml) and added N,N-diisopropylethyl amine(2.4 ml). This mixture was stirred at 90° C. for 90 mins. Isopropanolwas removed on rotavapour to obtain a residue. Work up (EtOAc/H2O)followed by purification on combiflash using a gradient mixture of EtOAcand Petether (7:93) as eluent afforded the titled compound as a pinksolid.

Intermediate 19:2-[1-(5-Fluoropyrimidin-2-yl)piperidin-4-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole

Intermediate 18 (0.28 g, 1.74 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.24 g, 1.0mmol) and potassium acetate (0.22 g, 2.2 mmol) were dissolved in dioxane(20 ml) under N₂ atmosphere. This mixture was degassed with nitrogen for30 mins and added Pd(dppO₂Cl₂.CH₂Cl₂ (24 mg, 0.03 mmol). Reactionmixture was stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycolumn chromatography on 60-120 mesh silica gel using a gradient mixtureof AcOEt and Petether (8:92) as eluent to afford the titled compound(0.15 g) as a pink solid.

Intermediate 20: 4-(Benzofuran-5-yl)-2-fluorobenzamide

Following the general procedure-1 the titled compound (200 mg) wasobtained from 5-Bromobenzofuran (200 mg, 1 mmol) and2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (320mg, 1.2 mmol) as a brown solid. ¹HNMR (δ ppm, DMSO-d₆, 400 MHz): 8.05(d, J 2.2, 2H), 8.02 (bs, 1H), 7.76-7.72 (m, 1H), 7.70-7.65 (m, 3H),7.64-7.58 (m, 3H), 7.01 (d, J 1.9, 1H).

Intermediate 21: 5-(4-carbamoyl-3-fluorophenyl)benzofuran-2-ylboronicacid

Intermediate 20 (100 mg. 0.4 mmol) was dissolved in THF (10 ml) and thismixture was cooled to −78° C. under N₂ atmosphere. n-BuLi (0.5 ml, 1.3mmol) was added to the above mixture and stirred at same temperature for20 mins Reaction mixture warmed to 0° C. and stirred for 2 hrs. Afterthat trisopropyl borate (88 mg, 0.47 mmol) was added and stirred thereaction for 16 h at rt. Reaction mass quenched with 2N HCl worked it up(EtOAC/H₂O) to afford the titled compound (110 mg) as a crude. It wasused in the next step without further purification.

Intermediate 22:1-Benzyl-N-(5-bromo-2-hydroxyphenyl)piperidine-4-carboxamide

1-Benzylpiperidine-4-carboxylic acid (29 g, 0.13 mol) dissolved in DCM(300 ml), cooled to 0° C. and added oxalyl chloride (17.3 ml, 0.2 mol).Catalytic amount of DMF was added to this mixture and strirred at rt for2 h. After 2 h, DCM removed on rotavapour and co-distilled the residuetwo times with DCM to obtainl-benzylpiperidine-4-carbonyl chloridequantitatively. 2-Amino-4-bromophenol (23 g, 0.12 mol) dissolved in DCMand added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. Thismixture stirred at rt for 30 mins and added1-benzylpiperidine-4-carbonyl chloride (29 g, 0.12 mol) in DCM (100 ml).After continuing stirring at rt for 2 h, DCM was removed on therotavapour to obtain the titled compound (47.6 g), which was used in thenext step without further purification.

Intermediate 23: 2-(1-Benzylpiperidin-4-yl)-5-bromobenzo[d]oxazole

Intermediate 22 (47.6 g, 0.122 mol) was dissolved in xylene (500 ml) andadded p-Toluenesulphonic acid (46 g, 0.24 mol). This mixture wasrefluxed for 20 h under a dean-stark condenser. Xylene was removed andpH of the residue was adjusted to 9 using aq NaHCO₃ solution. Work up(EtOAc/H2O) afforded the crude. Crude was purified by column on 60-120mesh silicagel using a gradient mixture of EtOAc and Petether (10:90) aseluent to afford the titled compound (11 g) as brown solid.

Intermediate 24:4-(2-(1-benzylpiperidin-4-yl)benzo[d]oxazol-5-yl)-2-fluorobenzamide

Following the general procedure-3, the titled compound (4.8 g) wasprepared from intermediate 23 (6 g, 16.2 mmol) and2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.7g, 17.8 mmol) as a brown solid.

Intermediate 25:2-Fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide

Intermediate 24 (100 mg, 0.23 mmol) dissolved in MeOH (10 ml) and addedPd/C (100 mg). This mixture was stirred under 60 Psi hydrogen atmospherein an autoclave for 16. After 16 h, reaction mass filtered throughcelite and celite was washed with MeOH. MeOH was removed on rotavapourto obtain the titled compound (80 mg) as an off-white solid.

Intermediate 26:5-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]Imidazole

4-bromobenzene-1,2-diamine (1.75 g, 9.39 mmol) and2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.39 mmol) were dissolvedin polyphosphoric acid (70 g). This mixture was heated at 195° C. forthree and half hours. Reaction mixture cooled to rt and diluted with icewater (100 ml). Aqueous layer basified with sodium hydroxide pellets topH 9. Work up (EtOAc/H₂O) followed by removal of EtOAc afforded thecrude. Crude was purified on combiflash with a gradient mixture of EtOAcand Petether (33:67) to obtain the titled compound (1.5 g) as anoff-white solid.

Intermediate 27:2-[2-Fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

Intermediate 26 (1.5 g, 4.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.34 g, 5.3mmol) and potassium acetate (1.32 g, 13.5 mmol) were dissolved indioxane (60 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (133 mg, 0.16 mmol).This mixture stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a mixture of AcOEt and Petether (33:67) to afford thetitled compound (880 mg) as an off-white solid.

Intermediate 28:5-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole

2-Amino-4-bromophenol (1.77 g, 9.4 mmol) and2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.4 mmol) were dissolvedin polyposphoric acid (60 g). This mixture was heated at 195° C. forthree and half hours. Reaction mixture cooled to rt and diluted with icewater (100 ml). Aqueous layer basified with sodium hydroxide pellets topH 9. Work up (EtOAc/H₂O) followed by evaporation of EtOAc afforded thecrude. Crude was purified on combiflash with a gradient mixture of EtOAcand Petether (33:67) to obtain the titled compound (2.8 g) as anoff-white solid.

Intermediate 29:2-[2-Fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole

Intermediate 28 (2.8 g, 7.6 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.5 g, 9.9mmol) and potassium acetate (2.46 g, 25.08 mmol) were dissolved indioxane (150 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (248 mg, 0.3 mmol).This mixture stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a gradient mixture of AcOEt and Petether (33:67) toafford the titled compound (1 g) as an off-white solid.

Intermediate 30:5-Bromo-7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole

2-Amino-4-bromo-6-fluorophenol (2.6 g, 9.7 mmol) and2-fluoro-4-(methylsulfonyl)benzoic acid (2.1 g, 9.7 mmol) were dissolvedin polyposphoric acid (63.5 g). This mixture was heated at 195° C. forthree and half hours. Reaction mixture cooled to rt and diluted with icewater (100 ml). Aqueous layer basified with sodium hydroxide pellets topH 9. Work up (EtOAc/H₂O) followed by evaporation of EtOAc afforded thecrude. Crude (3.1 g) was used in the next step without furtherpurification.

Intermediate 31:7-Fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole

Intermediate 30 (1.5 g, 3.87 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.28 g, 5mmol) and potassium acetate (1.25 g, 12.8 mmol) were dissolved indioxane (20 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (126 mg, 0.15 mmol).This mixture stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a gradient mixture of AcOEt and Petether (18:82) aseluent to afford the titled compound (620 mg) as an off-white solid.

Intermediate 32:N-(4-Bromo-2-fluorophenyl)-2-fluoro-4-(methylsulfonyl)benzamide

2-Fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) dissolved in DCM(10 ml), cooled to 0° C. and added oxalyl chloride (1.2 ml, 13.8 mmol).Catalytic amount of DMF was added to this mixture and strirred at rt for30 mins After 30 mins, DCM removed on rotavapour and co-distilled theresidue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoylchloride quantitatively. 4-Bromo-2-fluoroaniline (1.4 g, 7.37 mmol)dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under nitrogenatmosphere. This mixture stirred at rt for 30 mins and added2-fluoro-4-(methylsulfonyl)benzoyl chloride (2.08 g, 8.84 mmol). Aftercontinuing stifling at rt for 15 mins, reaction mixture diluted withwater and extracted with DCM. DCM layer washed with aq. NaHCO₃ and DCMremoved on rotavapour to obtain the solil. Solid was triturated withEt₂O and Petether mixture (4:1) to obtain the titled compound (1 g) as abrown solid.

Intermediate 33:N-(4-Bromo-2-fluorophenyl)-2-fluoro-4-(methylsulfonyl)benzothioamide

Intermediate 32 (1 g, 2.56 mmol) dissolved in toluene (10 ml) and addedP₂S₅ (0.57 g, 2.56 mmol). This mixture was refluxed for 18 h. Tolueneremoved on rotavapour to obtain the crude. Crude was purified by columnchromatography on 60-120 mesh silicagel using EtOAc and Petether (20:80)as eluent to afford the title compound (500 mg) as a yellow solid.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.02 (s, 1H), 7.92-7.85 (m, 2H), 7.69(dd, J 1.6, 8.1, 1H), 7.63 (dd, J 1.6, 9, 1H), 7.33-7.27 (m, 2H), 3.02(s, 3H).

Intermediate 34:6-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazole

Intermediate 33 (600 mg, 1.47 mmol) dissolved in DMF (7 ml) and addedNa₂CO₃ (156 mg, 1.47 mmol). This mixture stirred at 110° C. for 17 h.Work up (EtOAc/H₂O) afforded the crude. Crude was triturated withPetether and dried to obtain the titled compound (360 mg) as a whitesolid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.71-8.65 (m, 1H), 8.13 (d, J1.9, 1H), 8.01 (d, J 8.7, 1H), 7.91-7.83 (m, 2H), 7.66 (dd, J 1.9, 8.7,1H), 3.12 (s, 3H).

Intermediate 35:2-[2-Fluoro-4-(methylsulfonyl)phenyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole

Intermediate 34 (360 mg, 0.94 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (300 mg, 1.2mmol) and potassium acetate (300 mg, 1.2 mmol) were dissolved in dioxane(10 ml) under N₂ atmosphere. This mixture was degassed with nitrogen for30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (30 mg, 0.04 mmol). This mixturestirred at 105° C. for 12 h. Reaction mixture diluted with water andwork up (AcOEt/H₂O) afforded the crude. Crude was purified by combiflashusing a mixture of AcOEt and Petether (12:88) as eluent to afford thetitled compound (300 mg) as an off-white solid. ¹H-NMR (δ ppm, CDCl₃,400 MHz): 8.74-8.69 (m, 1H), 8.46 (s, 1H), 8.14 (d, J 8.2, 1H), 7.97(dd, J 1, 8.2, 1H), 7.91-7.83 (m, 2H), 3.12 (s, 3H), 1.38 (s, 12H).

Intermediate 36:N-(2,5-Dibromophenyl)-2-fluoro-4-(methylsulfonyl)benzamide

2-Fluoro-4-(methylsulfonyl)benzoic acid (1 g, 4.6 mmol) dissolved in DCM(15 ml), cooled to 0° C. and added oxalyl chloride (0.6 ml, 6.9 mmol).Catalytic amount of DMF was added to this mixture and strirred at rt for30 mins After 30 mins, DCM removed on rotavapour and co-distilled theresidue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoylchloride quantitatively. 2,5-Dibromoaniline (0.9 g, 3.59 mmol) dissolvedin DCM (10 ml) and added Pyridine (0.34 g, 4.30 mmol) under nitrogenatmosphere. This mixture stirred at rt for 30 mins and added2-fluoro-4-(methylsulfonyl)benzoyl chloride (1.01 g, 3.59 mmol). Aftercontinuing stirring at rt for 15 mins, reaction mass diluted with waterand extracted with DCM. DCM layer washed with aq. NaHCO₃ and DCM removedon rotavapour to obtain the solid. Solid was triturated with Et₂O andPetether mixture (4:1) to obtain the titled compound (1.6 g) as a brownsolid. ¹H-NMR (6 ppm, DMSO-d₆, 400 MHz): 10.34 (s, 1H), 8.34-7.99 (m,1H), 7.98-7.93 (m, 2H), 7.92-7.89 (m, 1H), 7.68 (d, J 8.6, 1H), 7.43(dd, J 2.4, 8.6, 1H), 3.33 (s, 3H).

Intermediate 37:N-(2,5-Dibromophenyl)-2-fluoro-4-(methylsulfonyl)benzothioamide

Intermediate 36 (1.5 g, 3.34 mmol) dissolved in toluene (20 ml) andadded P₂S₅ (0.74 g, 3.34 mmol). This mixture was refluxed for 18 h.Toluene removed on rotavapour to obtain the crude. Crude was purified bycolumn chromatography on 60-120 mesh silicagel using EtOAc and Petether(20:80) as eluent to afford the title compound (480 mg) as a yellowsolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.26 (s, 1H), 7.94-7.83 (m,3H), 7.78-7.72 (m, 2H), 7.55 (dd, J 2.3, 8.6, 1H), 3.32 (s, 3H).

Intermediate 38:5-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazole

Intermediate 37 (0.48 g, 1.03 mmol) dissolved in N-Methylpyrrolidinone(0.97 ml) and added NaH (52 mg, 2.2 mmol). This mixture was stirred at140° C. for 3 h. Reaction mixture cooled to rt and diluted with water toobtain the solid. Solid was filtered and dried to obtain the crude.Crude was purified on column chromatography using 60-120 mesh silicageland DCM as eluent to afford the titled compound (260 mg) as a whitesolid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.71-8.66 (m, 1H), 8.32 (d, J1.7, 1H), 7.92-7.83 (m, 3H), 7.59 (dd, J 1.8, 8.6, 1H), 3.13 (s, 3H).

Intermediate 39:2-[2-Fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole

Intermediate 38 (360 mg, 0.94 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (220 mg,0.88 mmol) and potassium acetate (220 mg, 2.2 mmol) were dissolved indioxane (10 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (22 mg, 0.03 mmol).This mixture stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a mixture of AcOEt and Petether (12:88) as eluent toafford the titled compound (230 mg) as a yellow solid. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.73-8.67 (m, 1H), 8.62 (s, 1H), 7.98 (d, J 8, 1H),7.90-7.81 (m, 3H), 3.12 (s, 3H), 1.39 (s, 12H).

Intermediate 40:6-Bromo-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole

2-amino-5-bromophenol (1.72 g, 9.2 mmol) and2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) were dissolvedin polyposphoric acid (30 g). This mixture was heated at 195° C. forthree and half hours. Reaction mixture cooled to rt and diluted with icewater (100 ml). Aqueous layer basified with sodium hydroxide pellets topH 9. Solid that formed was filtered and dried to obtain the crude.Crude was purified by combiflash using a gradient mixture of EtOAc andPetether (1:3) as eluent to afford the titled compound (450 mg) as adark brown solid.

Intermediate 41:2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole

Intermediate 40 (1.5 g, 4.1 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.35 g,5.29 mmol) and potassium acetate (1.32 g, 13.45 mmol) were dissolved indioxane (10 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (133 mg, 0.16 mmol).This mixture stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a gradient mixture of AcOEt and Petether (1:3) aseluent to afford the titled compound (500 mg) as a pink solid.

Intermediate 42: N-(5-Br omo-2-hy dr oxyphenyl)-4-(trifluoromethyl)benzamide

4-(Trifluoromethyl)benzoic acid (1 g, 5.3 mmol) dissolved in DCM (10ml), cooled to 0° C. and added oxalyl chloride (0.7 ml, 7.9 mmol).Catalytic amount of DMF was added to this mixture and strirred at rt for30 mins. After 30 mins, DCM removed on rotavapour and co-distilled theresidue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloridequantitatively. 2-Amino-4-bromophenol (0.8 g, 4.25 mmol) dissolved inDCM (20 ml) and added Pyridine (0.4 ml, 5.1 mmol) under nitrogenatmosphere. This mixture stirred at rt for 30 mins and added4-(trifluoromethyl)benzoyl chloride (1.06 g, 5.1 mmol). After continuingstirring at rt for 15 mins, reaction mass diluted with water andextracted with DCM. DCM layer washed with aq. NaHCO₃ and DCM removed onrotavapour to obtain the solid. Solid was triturated with Et₂O andPetether mixture (4:1) to obtain the titled compound (1 g) as a brownsolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.15 (bs, 1H), 9.75 (s, 1H),8.13 (d, J 8.1, 2H), 7.92-7.87 (m, 3H), 7.20 (dd, J 2.5, 8.6, 1H), 6.88(d, J 8.6, 1H).

Intermediate 43: 5-bromo-2-[4-(trifluoromethyl)phenyl]benzo[d]oxazole

Intermediate 42 (1 g, 2.77 mmol) was dissolved in 1,4-Dioxane and addedPhosphorus oxychloride (0.76 ml, 8.3 mmol). This mixture was refluxedfor 2 h. 1,4-Dioxane removed on rotavapour to obtain the residue.Residue was washed with water to obtain solid. Solid was filtered anddried to obtain the titled compound (630 mg) as an off-white solid.¹H-NMR (6 ppm, CDCl₃, 400 MHz): 8.35 (d, J 8.2, 2H), 7.93 (d, J 1.5,1H), 7.79 (d, J 8.3, 2H), 7.52-7.49 (m, 2H).

Intermediate 44:5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole

Intermediate 43 (630 mg, 1.84 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (600 mg, 2.4mmol) and potassium acetate (590 mg, 6.1 mmol) were dissolved in1,4-dioxane (10 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (60 mg, 0.08 mmol).This mixture stirred at 105° C. for 12 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a mixture of AcOEt and Petether (8:92) as eluent toafford the titled compound (400 mg) as a yellow solid. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.38 (d, J 8.1, 2H), 8.25 (s, 1H), 7.86 (dd, J 1, 7.9,1H), 7.78 (d, J 8.3, 2H), 7.59 (d, J 8.6, 1H), 1.38 (s, 12H).

Intermediate 45: N-(4-Bromo-2-hydroxyphenyl)-4-(difluoromethyl)benzamide

4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml),cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalyticamount of DMF was added to this mixture and strirred at rt for 30 mins.After 30 mins, DCM removed on rotavapour and co-distilled the residuetwo times with DCM to obtain 4-(difluoromethyl)benzoyl chloridequantitatively. 2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved inDCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogenatmosphere. This mixture stirred at rt for 30 mins and added4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuingstirring at rt for 15 mins, reaction mass diluted with water andextracted with DCM. DCM layer washed with aq. NaHCO₃ and DCM removed onrotavapour to obtain the solid. Solid was triturated with Et₂O andPetether mixture (4:1) to obtain the titled compound (0.5 g) as a yellowsolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H),8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t,J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H).

Intermediate 46: 6-Bromo-2-[4-(difluoromethyl)phenyl]benzo[d]oxazole

N-(4-Bromo-2-hydroxyphenyl)-4-(difluoromethyl)benzamide (0.5 g, 1.5mmol) was dissolved in 1,4-Dioxane (10 ml) and added Phosphorusoxychloride (0.4 ml, 4.4 mmol). This mixture was refluxed for 2 h.1,4-Dioxane removed on rotavapour to obtain the residue. Residue waswashed with water to obtain solid. Solid was purified by column on60-120 mesh silica gel using DCM as eluent to obtain the titled compound(130 mg) as an off-white solid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.28 (d,J 8.4, 2H), 7.74 (d, J 1.7, 1H), 7.65-7.58 (m, 3H), 7.46 (dd, J 1.8,8.4, 1H), 6.68 (t, J 56.2, 1H).

Intermediate 47:2-[4-(Difluoromethyl)phenyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole

Intermediate 46 (130 mg, 0.4 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (130 mg,0.52 mmol) and potassium acetate (110 mg, 1.2 mmol) were dissolved in1,4-dioxane (15 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (13 mg, 0.02 mmol).This mixture stirred at 105° C. for 4 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a mixture of AcOEt and Petether (8:92) as eluent toafford the titled compound (100 mg) as a yellow solid.

Intermediate 48: Tert-butyl4-{2-[4-(difluoromethyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate

Following the general procedure-2, the titled compound was prepared fromintermediate 47 (0.1 g, 0.27 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (89mg, 0.27 mmol) as an off-white solid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):8.34 (d, J 8.4, 2H), 7.72 (d, J 8.4, 1H), 7.67 (d, J 8.2, 2H), 7.58 (d,J 1.4, 1H), 7.43 (dd, J 1.6, 8.4, 1H), 6.72 (t, J 56.2, 1H), 6.12 (bs,1H), 4.12 (d, J 2.7, 2H), 3.68 (t, J 5.6, 2H), 2.60 (bs, 2H), 1.50 (s,9H).

Intermediate 49: tert-butyl4-(2-p-tolylbenzo[d]oxazol-6-yl)piperidine-1-carboxylate

Intermediate 48 (45 mg, 0.14 mmol) dissolved in MeOH (10 ml) and addedPd/C (5%) (100 mg). This mixture was stirred under 60 Psi hydrogenpressure for 15 h in an autoclave. After completion of the reaction,reaction mixture filtered through a bed of celite and celite was washedwith MeOH. Combined MeOH layers were removed on rotavapour to obtain theresidue. Residue was triturated with petether to obtain the titledcompound (40 mg) as an off-white solid. MS (m/z): 393.2 [M+f1]⁺.

Intermediate 50: Tert-butyl4-(2-aminobenzo[d]oxazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

5-Bromobenzo[d]oxazol-2-amine (824 mg, 3.9 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1 (2H)-carboxylate(1.8 g, 5.8 mmol), Potassium fluoride (674 mg, 11.61 mmol) weredissolved in DMF under N₂ atmosphere. This mixture was purged with N₂for 30 mins Pd(dppf)₂Cl₂.CH₂Cl₂ (252 mg, 0.3 mmol) was added to theabove mixture and again purged with N₂ for 30 mins. The reaction mixturewas stirred at 90° C. for 12 h. Work up (EtOAc/H2O) followed by columnpurification on combiflash using a gradient mixture of EtOAc andPetether (1:1) as eluent afforded the titled compound (550 mg) as anoff-white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.38-7.36 (m, 2H),7.26-7.22 (m, 2H), 7.02 (d, J 7.9, 1H), 6.05 (s, 1H), 4.01-3.90 (m, 2H),3.49-3.55 (m, 2H), 2.50-2.40 (m, 2H), 1.50 (s, 9H).

Intermediate 51: Tert-butyl4-(2-aminobenzo[d]oxazol-5-yl)piperidine-1-carboxylate

Intermediate 50 (550 mg, 0.14 mmol) dissolved in MeOH (25 ml) and addedPd/C (5%) (700 mg). This mixture was stirred under 80 Psi hydrogenpressure for 12 h in an autoclave. After completion of the reaction,reaction mixture filtered through a bed of celite and celite was washedwith MeOH. MeOH was removed on rotavapour to obtain the residue. Residuewas triturated with petether to obtain the titled compound (400 mg) asan off-white solid.

Intermediate 52: Tert-butyl4-(2-bromobenzo[d]oxazol-5-yl)piperidine-1-carboxylate

Intermediate 51 (400 mg, 1.3 mmol) was dissolved in acetonitrile (50 ml)and added CuBr₂ (563 mg, 2.5 mmol). This mixture stirred at rt for 15mins Tert-Butyl nitrite (259 mg, 2.5 mmol) was added to the abovemixture for 5 mins and stirred at 45° C. for 2 h. Work up (DCM/H₂O)followed by purification on combiflash using a gradient mixture of EtOAcand Petether (1:3) as eluent afforded the titled compound (130 mg) as anoff-white solid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.28 (bs, 1H), 7.41 (s,1H), 6.91 (s, 1H), 4.35-4.19 (m, 2H), 3.21-3.10 (m, 1H), 2.85 (t, J11.3, 2H), 1.90-1.80 (m, 2H), 1.60-1.40 (m, 11H).

Intermediate 53:N-(4-bromo-2-hydroxyphenyl)-4-(trifluoromethyl)benzamide

4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved in DCM (20ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol).Catalytic amount of DMF was added to this mixture and strirred at rt for30 mins. After 30 mins, DCM removed on rotavapour and co-distilled theresidue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloridequantitatively. 2-Amino-5-bromophenol (0.71 g, 3.8 mmol) dissolved inDCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogenatmosphere. This mixture stirred at rt for 30 mins and added4-(trifluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After continuingstirring at rt for 15 mins, reaction mass diluted with water andextracted with DCM. DCM layer washed with aq. NaHCO₃ and DCM removed onrotavapour to obtain the solid. Solid was triturated with Et₂O andPetether mixture (4:1) to obtain the titled compound (0.6 g) as a yellowsolid.

Intermediate 54: 6-bromo-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole

Intermediate 53 (940 mg, 2.6 mmol) was dissolved in xylene (25 ml) andadded p-Toluenesulphonic acid (991 mg, 5.22 mmol). This mixture wasrefluxed to 160° C. for 12 h under a dean-stork condenser. Xyleneremoved from the reaction mixture and basified the residue with aq.NaHCO₃ (30 ml). Work up (EtOAc/H₂O) followed by purification withcombiflash using a gradient mixture of EtOAc and Petether (5:95) aseluent to afford the titled compound (650 mg) as an Off-White solid.

Intermediate 55:6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[4-(trifluoromethyl)phenyl]benzo[d]oxazole

Intermediate 54 (630 mg, 1.84 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (600 mg, 2.4mmol) and potassium acetate (590 mg, 3.3 mmol) were dissolved in1,4-dioxane (30 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (60 mg, 0.074 mmol).This mixture stirred at 105° C. for 17 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a mixture of AcOEt and Petether (20:80) as eluent toafford the titled compound (420 mg) as an off-white solid. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.39 (d, J 8.1, 2H), 8.05 (s, 1H), 7.84 (dd, J0.8, 8, 1H), 7.82-7.76 (m, 3H), 1.38 (s, 12H).

Intermediate 56:N-(5-bromo-2-hydroxypyridin-3-yl)-4-(trifluoromethyl)benzamide

4-(Trifluoromethyl)benzoic acid (2.45 g, 12.9 mmol) dissolved in DCM (30ml), cooled to 0° C. and added oxalyl chloride (3.4 ml, 38.6 mmol).Catalytic amount of DMF was added to this mixture and strirred at rt for30 mins After 30 mins, DCM removed on rotavapour and co-distilled theresidue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloridequantitatively. 2-Hydroxy-3-amino-5-bromopyridine (2.4 g, 11.1 mmol)dissolved in DCM (15 ml) and added Pyridine (1.74 g, 22 mmol) undernitrogen atmosphere. This mixture stirred at rt for 30 mins and added4-(trifluoromethyl)benzoyl chloride (2.4 g, 13.3 mmol). After continuingstirring at rt for 30 mins, reaction mass diluted with water andextracted with DCM. DCM removed on rotavapour to obtain the crude. Crudewas purified on column using 60-120 mesh silica gel and a gradientmixture of MeOH and DCM (2:98) as eluent to afford the titled compound(2.1 g) as a brown solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.43 (bs,1H), 9.58 (s, 1H), 8.37 (d, J 2.6, 1H), 8.09 (d, J 8.2, 2H), 7.91 (d, J8.2, 2H), 7.48 (d, J 2.6, 1H).

Intermediate 57:6-bromo-2-(4-(trifluoromethyl)phenyl)oxazolo[5,4-b]pyridine

Intermediate 56 (2.1 g, 5.4 mmol) was dissolved in Dioxane (30 ml) andadded POCl₃ (1.5 ml). This mixture was refluxed for 5 h. After 5 h,dioxane was removed on rotavapour to obtain the residue. Work up(EtOAc/H₂O) of the residue afforded the crude. Crude was purified bycolumn on 60-120 mesh silica gel using DCM as eluent to afford thetitled compound (1.2 g). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.46 (d, J 2.1,1H), 8.41 (d, J 8.2, 2H), 8.24 (d, J 2.1, 1H), 7.83 (d, J 8.2, 2H).

Intermediate 58:6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridine

Intermediate 57 (1.2 g, 3.5 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (973 mg, 3.8mmol) and potassium acetate (1.03 g, 10.5 mmol) were dissolved in1,4-dioxane (40 ml) under N₂ atmosphere. This mixture was degassed withnitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (113 mg, 0.14 mmol).This mixture stirred at 105° C. for 15 h. Reaction mixture diluted withwater and work up (AcOEt/H₂O) afforded the crude. Crude was purified bycombiflash using a gradient mixture of AcOEt and Petether (5:95) aseluent to afford the titled compound (1.2 g) as an off-white solid.¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.77 (d, J 1.5, 1H), 8.46 (d, J 1.5,1H), 8.41 (d, J 8.1, 2H), 7.80 (d, J 8.1, 2H), 1.38 (s, 12H).

General Procedure-1 for Suzuki Coupling:

Aryl bromide (1 eq.) was dissolved in Dioxane and water (5:1) and addedarylboronic acid (1.3 eq), Pd(PPh₃)₄ (0.08 eq) and Na₂CO₃ (3.3 eq).Reaction mixture degassed with N₂ for 30 mins and refluxed until boththe starting materials disappeared. Work-up (H₂O/AcOEt) and purificationgave the desired product.

General Procedure-2 for Suzuki Coupling:

Aryl bromide (1 eq), arylboronic acid (1 eq.), Sodium carbonate (3 eq)dissolved in DMF and water (4:1) and degassed with N₂ for 15 mins. Tothis mixture Pd(dppf)₂Cl₂.CH₂Cl₂ (0.08 eq) was added and degassed againwith N₂ for 15 mins. This mixture was irradiated in micro wave for 105mins, at 80° C. Work-up (H₂O/AcOEt) and purification gave the desiredproduct.

General Procedure-3 for Suzuki Coupling:

Same as General Procedure-2 except that KF was used instead of Na₂CO₃

General Procedure-4 for Suzuki Coupling:

Same as General Procedure-2 except that Dioxane was used instead of DMF.

Example 1 2-[1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole

Following the General Procedure-1, the titled compound (25 mg) wasprepared from Intermediate 2 (80 mg, 0.199 mmol) and Intermediate 3 (79mg, 0.26 mmol) as a yellow solid. M.P.: 186.5-190° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 12.41 (d, J 4, 1H), 8.26 (s, 2H), 7.90-7.80 (m, 3H),7.79-7.50 (m, 2H), 7.40-7.32 (m, 1H), 4.66 (d, J 13.1, 2H), 3.29 (s,3H), 3.21 (t, J 8.3, 1H), 3.09 (t, J 11.7, 2H), 2.43 (q, J 7.73, 2H),2.06 (d, J 12.5, 2H), 1.82-1.71 (m, 2H), 1.13 (t, J 7.5, 3H).

Example 2 Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (40 mg) wasprepared from Intermediate 4 (100 mg, 0.25 mmol) and Intermediate 3 (98mg, 0.33 mmol) as a yellow solid. M.P.: 88-92° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 12.39 (s, 1H), 7.89-7.81 (m, 3H), 7.69-7.58 (m, 2H),7.40-7.32 (m, 1H), 4.01 (d, J 12.5, 2H), 3.30 (s, 3H), 3.12-3.05 (m,1H), 3.00-2.88 (m, 2H), 2.00 (d, J 11.8, 2H), 1.76-1.55 (m, 2H), 1.41(s, 9H).

Example 3 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl] benzo[d]oxazole

Following the General Procedure-1, the titled compound (30 mg) wasprepared from Intermediate 6 (80 mg, 0.21 mmol) and Intermediate 3 (80mg, 0.27 mmol) as an off-white solid. M.P.: 247-250° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.20 (s, 2H), 7.86 (s, 1H), 7.80 (m, 1H), 7.79-7.74 (m,1H), 7.66 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.75(d, J 13.4, 2H), 3.35-3.15 (m, 3H), 3.11 (s, 3H), 2.47 (q, J 7.6, 2H),2.31-2.22 (m, 2H), 2.09-1.94 (m, 2H), 1.20 (t, J 7.6, 3H).

Example 4 tert-butyl4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (40 mg) wasprepared from Intermediate 7 (150 mg, 0.4 mmol) and Intermediate 3 (154mg, 0.51 mmol) as an off-white solid. M.P.: 144-147° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 7.87 (s, 1H), 7.82 (d, J 8, 1H), 7.77 (dd, J 1.4, 9.4,1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.15(d, J 7.7, 2H), 3.22-3.10 (m, 4H), 3.00 (t, J 11.3, 2H), 2.21-2.12 (m,2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).

Example 5 Tert-butyl4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate

Tert-butyl4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate(85 mg, 0.17 mmol) dissolved in THF (15 ml) and cooled to 0° C. Sodiumhydride (9 mg, 0.342 mmol) added to the above mixture and stirred at thesame temperature for 30 mins. To this mixture methyl iodide (48 mg,0.342 mmol) added at same temperature and stirred the reaction mixtureat rt for 3 h. Reaction mixture diluted with ice and worked up(EtOAc/H₂O). Crude was purified by column chromatography on 60-120 meshsilica gel using EtOAc: Petether (3:1) as eluent to afford the titlecompound (50 mg) as an orange solid. M.P.: 85-88° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 7.85-7.75 (m, 2H), 7.73-7.64 (m, 2H), 7.56-7.51 (m,1H), 7.50-7.45 (m, 1H), 4.39-4.21 (m, 2H), 3.82 (s, 3H), 3.11 (s, 3H),3.10-3.00 (m, 2H), 3.00-2.88 (m, 2H), 2.05-1.93 (m, 3H), 1.48 (s, 9H).

Example 6 Tert-butyl4-{6-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (21 mg) wasprepared from Intermediate 10 (100 mg, 0.26 mmol) and Intermediate 3(102 mg, 0.34 mmol) as an off-white solid. M.P.: 174-178.3° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 7.85-7.75 (m, 3H), 7.73-7.64 (m, 2H), 7.50 (d, J8.2, 1H), 4.15 (d, J 12.4, 2H), 3.20-3.10 (m, 4H), 3.0 (t, J 12.5, 2H),2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).

Example 7 Isopropyl4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Tert-butyl4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(200 mg, 0.42 mmol) dissolved in DCM and added Trifluoroacetic acid(0.75 ml). This mixture was stirred at rt for 2 h. DCM removed from thereaction mixture to obtain5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (190 mg).5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (190 mg, 0.39 mmol) was dissolved in DCM (20 ml)and added TEA (0.43 ml, 3.12 mmol). This mixture stirred at rt for 30mins and added isopropyl chloroformate in toluene (0.095 g, 0.78 mmol).After 1 h, reaction mass diluted with water and extracted with DCM.Removal of DCM afforded crude. Crude was purified by combiflash using amixture of EtOAc and Petether (35:65) as eluent to afford the titledcompound (120 mg) as a pale-yellow solid. M.P.: 96.5-101.2° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 7.87 (s, 1H), 7.81 (dd, J 1.7, 8, 1H), 7.80-7.75(m, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H),4.94 (septet, J 6.2, 1H), 4.19 (d, J 10.9, 2H), 3.22-3.13 (m, 1H), 3.12(s, 3H), 3.04 (t, J 10.9, 2H), 2.22-2.14 (m, 2H), 2.00-1.88 (m, 2H),1.26 (d, J 6.2, 6H).

Example 8 Tert-butyl4-{7-fluoro-5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (50 mg) wasprepared from Intermediate 12 (200 mg, 0.50 mmol) and Intermediate 3(151 mg, 0.50 mmol) as an off-white solid. M.P.: 155.3-158.4° C. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): 7.82 (dd, J 1.8, 8.1, 1H), 7.78 (dd, J 1.7,9.4, 1H), 7.69-7.63 (m, 2H), 7.29 (td, 1.3, 10.6, 1H), 4.16 (d, J 11.2,2 H), 3.22-3.16 (m, 1H), 3.11 (s, 3H), 3.00 (t, J 13.3, 2H), 2.21-2.14(m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).

Example 9 Tert-butyl4-[5-(4-cyanophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (45 mg) wasprepared from Intermediate 7 (140 mg, 0.37 mmol) and4-Cyanophenylboronic acid (53 mg, 0.37 mmol) as an off-white solid.M.P.: 137.3-141.2° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.88 (d, 1.4, 1H),7.74 (dd, J 1.8, 8.5, 2H), 7.69 (dd, J 1.8, 8.5, 2H), 7.58 (d, J 8.5,1H), 7.53 (dd, J 1.8, 8.5, 2H), 4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H),3.00 (t, J 11.2, 2H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s,9H).

Example 10 Tert-butyl4-{5-[3-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (30 mg) wasprepared from Intermediate 8 (100 mg, 0.23 mmol) and4-bromo-2-fluoro-1-(methylsulfonyl)benzene (70 mg, 0.37 mmol) as anoff-white solid. M.P.: 174.3-177.5° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):8.03 (t, J 7.9, 1H), 7.88 (d, J 1.6, 1H), 7.61-7.51 (m, 3H), 7.46 (dd, J1.6, 11.1, 1H), 4.15 (d, J 11.2, 2H), 3.26 (s, 3H), 3.20-3.11 (m, 1H),3.00 (t, J 12.2, 2H), 2.20-2.12 (m, 2H), 1.98-1.84 (m, 2H), 1.48 (s,9H).

Example 11 Tert-butyl4-{5-[4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (80 mg) wasprepared from Intermediate 8 (200 mg, 0.47 mmol) and1-(4-bromophenyl)-1H-tetrazole (100 mg, 0.44 mmol) as a brown solid.M.P.: 207-211° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 9.02 (s, 1H), 7.91 (d,J 1.2, 1H), 7.82-7.79 (m, 4H), 7.62-7.55 (m, 2H), 4.16 (d, J 10.6, 2H),3.21-3.12 (m, 1H), 3.00 (t, J 12.3, 2H), 2.20-2.14 (m, 2H), 2.00-1.88(m, 2H), 1.48 (s, 9H).

Example 12 Tert-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (10 mg) wasprepared from Intermediate 8 (200 mg, 0.47 mmol) and1-(4-bromo-3-fluorophenyl)-1H-tetrazole (110 mg, 0.45 mmol) as a brownsolid. M.P.: 203-207° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 9.04 (s, 1H),7.88 (s, 1H), 7.71-7.58 (m, 4H), 7.52 (td, 1.6, 8.4, 1H), 4.16 (d, J10.8, 2H), 3.21-3.12 (m, 1H), 3.00 (t, J 12.2, 2H), 2.21-2.13 (m, 2H),2.00-1.85 (m, 2H), 1.48 (s, 9H).

Example 13 Tert-butyl4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (40 mg) wasprepared from Intermediate 7 (150 mg, 0.4 mmol) and4-(trifluoromethyl)phenylboronic acid (74 mg, 0.39 mmol) as an off-whitesolid. M.P.: 166-169° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.88 (d, J 1.2,1H), 7.73-7.67 (m, 4H), 7.59-7.52 (m, 2H), 4.15 (d, J 10, 2H), 3.20-3.10(m, 1H), 3.00 (t, J 11.6, 2H), 2.21-2.12 (m, 2H), 1.99-1.86 (m, 2H),1.48 (s, 9H).

Example 14 Isopropyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Tert-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(120 mg, 0.26 mmol) dissolved in DCM and added Trifluoroacetic acid (0.5ml). This mixture was stirred at rt for 2 h. DCM removed from thereaction mixture to obtain5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoro ac etate (150 mg).5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (70 mg, 0.17 mmol) was dissolved in DCM (15 ml)and added TEA (0.2 ml, 1.4 mmol). This mixture stirred at rt for 30 minsand added isopropyl chloroformate in toluene (42 mg, 0.34 mmol). After 1h, reaction mass diluted with water and extracted with DCM. Removal ofDCM afforded crude. Crude was purified by combiflash using a mixture ofEtOAc and Petether (35:65) as eluent to afford the titled compound (30mg) as an off-white solid. M.P.: 168-171° C. ¹H-NMR (δ ppm, CDCl₃, 400MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.68 (t, J 8.2, 1H), 7.64-7.58 (m,3H), 7.54-7.50 (m, 1H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H),3.22-3.14 (m, 1H), 3.04 (t, J 11.2, 2H), 2.22-2.15 (m, 2H), 2.00-1.88(m, 2H), 1.26 (d, J 6.2, 6H).

Example 15 Tert-butyl4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (22 mg) wasprepared from Intermediate 8 (100 mg, 0.23 mmol) and1-(4-bromo-2-fluorophenyl)-1H-tetrazole (56 mg, 0.23 mmol) as apale-yellow solid. M.P.: 154-159° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):9.14 (d, J 2.5, 1H), 8.04 (t, J 7.8, 1H), 7.91 (d, J 3.9, 1H), 7.64-7.54(m, 4H), 4.16 (d, J 10, 2H), 3.21-3.13 (m, 1H), 3.01 (t, J 11.9, 2H),2.21-2.12 (m, 2H), 2.00-1.87 (m, 2H), 1.48 (s, 9H).

Example 162-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazole

Tert-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Trifluoroaceticacid (0.5 ml). This mixture was stirred at rt for 2 h. DCM removed fromthe reaction mixture to obtain5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (150 mg).5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (70 mg, 0.15 mmol) was dissolved in IPA (10 ml),added DiPEA (0.25 ml, 1.2 mmol) and stirred at rt for 30 mins2-Chloro-5-ethyl piperidine was added to the above reaction mixture andheated the reaction mixture to 90° C. for overnight. After completion ofthe reaction, work-up (EtOAc/H₂O) followed by purification on combiflashusing the gradient mixture of ethyl acetate and petether (1:1) as eluentafforded the titled compound (20 mg) as an off-white solid. M.P.:188-192° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 9.03 (s, 1H), 8.20 (s, 2H),7.88 (s, 1H), 7.68 (t, J 8.2, 1H), 7.65-7.58 (m, 3H), 7.54-7.49 ((m,1H), 4.80-4.70 (m, 2H), 3.33-3.23 (m, 1H), 3.22 (t, J 14, 2H), 2.48 (q,J 7.6, 2H), 2.30-2.22 (m, 2H), 2.07-1.95 (m, 2H), 1.20 (t, J 7.6, 3H).

Example 17 Tert-butyl4-[5-(4-cyano-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-2, the titled compound (70 mg) wasprepared from Intermediate 8 (150 mg, 0.35 mmol) and4-bromo-2-fluorobenzonitrile (70 mg, 0.35 mmol) as a white solid. M.P.:138-142° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.87 (d, J 1.6, 1H),7.72-7.68 (m, 1H), 7.59 (d, J 8.5, 1H), 7.53-7.42 (m, 3H), 4.15 (d, J10.6, 2H), 3.20-3.11 (m, 1H), 3.00 (t, J 11.8, 2H), 2.2-2.12 (m, 2H),1.98-1.86 (m, 2H), 1.56 (S, 9H).

Example 18 Isopropyl4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Tert-butyl4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Trifluoroaceticacid (0.5 ml). This mixture was stirred at rt for 2 h. DCM removed fromthe reaction mixture to obtain5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (120 mg).5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (120 mg, 0.25 mmol) was dissolved in DCM (15 ml)and added TEA (0.27 ml, 2 mmol). This mixture stirred at rt for 30 minsand added isopropyl chloroformate in toluene (61 mg, 0.34 mmol). After 1h, reaction mass diluted with water and extracted with DCM. Removal ofDCM afforded crude. Crude was purified by combiflash using a mixture ofEtOAc and Petether (35:65) as eluent to afford the titled compound (20mg) as an off-white solid. M.P.: 187-191° C. ¹H-NMR (δ ppm, CDCl₃, 400MHz): 9.14 (d, J 2.6, 1H), 8.02 (t, J 8.2, 1H), 7.90 (d, J 1.4, 1H),7.63-7.55 (m, 4H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H),3.22-3.14 (m, 1H), 3.04 (t, J 11.4, 2H), 2.18 (d, J 10.8, 2H), 2.00-1.88(m, 2H), 1.26 (d, J 6.2, 6H).

Example 19 Tert-butyl4-{5-[3-fluoro-4-(1H-tetrazol-5-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-2, the titled compound (6 mg) wasprepared from Intermediate 8 (150 mg, 0.35 mmol) and intermediate 17 (85mg, 0.35 mmol) as a brown solid. M.P.: 163-167° C. ¹H-NMR (δ ppm, CDCl₃,400 MHz): 8.15 (s, 1H), 8.11 (t, J 8, 1H), 7.86 (d, J 12.2, 1H),7.82-7.77 (m, 3H), 3.95 (d, J 13.4, 2H), 3.42-3.35 (m, 1H), 3.05-2.92(m, 2H), 2.14-2.06 (m, 2H), 1.76-1.64 (m, 2H), 1.41 (s, 9H).

Example 20 Tert-butyl4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-2, the titled compound (25 mg) wasprepared from Intermediate 7 (150 mg, 0.4 mmol) and2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (110mg, 0.4 mmol) as a brown solid. M.P.: 169-171° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.03 (s, 1H), 7.87 (bs, 1H), 7.82-7.75 (m, 2H),7.73-7.66 (m, 2H), 7.59 (bs, 1H), 7.52 (d, J 7.9, 1H), 3.94 (d, J 12.9,2H), 3.30-3.22 (m, 1H), 3.08-2.92 (m, 2H), 2.09 (d, J 10.6, 2H),1.75-1.63 (m, 2H), 1.40 (s, 9H).

Example 21 Tert-butyl4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (25 mg) wasprepared from Intermediate 8 (150 mg, 0.35 mmol) and4-bromo-2-fluorobenzamide (77 mg, 0.35 mmol) as a white solid. M.P.:202-206° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.22 (t, J 8.3, 1H), 7.89(s, 1H), 7.59-7.49 (m, 3H), 7.37 (dd, J 1.6, 13.24, 1H), 6.71 (d, J 9.5,1H), 5.85 (s, 1H), 4.15 (d, J 10.7, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J11.8, 2H), 2.20-2.12 (m, 2H), 1.99-1.85 (m, 2H), 1.48 (s, 9H).

Example 22 Tert-butyl4-[5-(3-fluoro-4-isopropoxyphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (25 mg) wasprepared from Intermediate 8 (150 mg, 0.35 mmol) and4-bromo-2-fluoro-1-isopropoxybenzene (81 mg, 0.35 mmol) as a whitesolid. M.P.: 124-128° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.81 (d, J 1.4,1H), 7.53-7.45 (m, 2H), 7.35-7.27 (m, 2H), 7.05 (t, J 8.6, 1H), 4.58(septet, J 6.1, 1H), 4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H), 2.99 (t, J11.7, 2H), 2.15 (dd, J 2.8, 13.4, 2H), 1.97-1.86 (m, 2H), 1.56 (s, 9H),1.39 (d, J 6.1, 6H).

Example 23 Cyclobutyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Tert-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(300 mg, 0.65 mmol) dissolved in DCM (15 ml) and added Trifluoroaceticacid (1.5 ml). This mixture was stirred at rt for 2 h. DCM removed fromthe reaction mixture to obtain5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (300 mg).5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml)and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rtfor 1 h. To this mixture added cyclobutanol (0.05 ml, 0.63 mmol) and TEA(0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up(EtOAc/H₂O) and purification of the crude by combiflash with gradientmixture of ethyl acetate and petether (1:1) as eluent afforded thetitled compound (25 mg) as an off-white solid. M.P.: 165-169° C. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H),7.55-7.50 (m, 1H), 4.96 (septet, J 7.8, 1H), 4.20 (d, J 12.4, 2H),3.22-3.13 (m, 1H), 3.06 (t, J 9.8, 2H), 2.40-2.30 (m, 2H), 2.24-2.15 (m,2H), 2.15-2.02 (m, 2H), 2.00-1.90 (m, 2H), 1.78 (q, J 10, 2H).

Example 24 Sec-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Tert-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(250 mg, 0.54 mmol) dissolved in DCM (15 ml) and added Trifluoroaceticacid (1 ml). This mixture was stirred at rt for 2 h. DCM removed fromthe reaction mixture to obtain5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoro acetate (260 mg).5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml)and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rtfor 1 h. To this mixture added 2-butanol (46 mg, 0.63 mmol) and TEA(0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up(EtOAc/H₂O) and purification of the crude by combiflash with gradientmixture of ethyl acetate and petether (1:1) as eluent afforded thetitled compound (30 mg) as an off-white solid. M.P.: 118-122° C. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H),7.55-7.50 (m, 1H), 4.82-4.73 (m, 1H), 4.21 (d, J 12.7, 2H), 3.24-3.13(m, 1H), 3.06 (t, J 11.6, 2H), 2.19 (d, J 10.9, 2H), 2.00-1.88 (m, 2H),1.69-1.50 (m, 2H), 1.24 (d, J 6.2, 3H), 0.92 (t, J 7.4, 3H).

Example 25 Pentan-3-yl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Tert-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(250 mg, 0.54 mmol) dissolved in DCM (15 ml) and added Trifluoroaceticacid (1 ml). This mixture was stirred at rt for 2 h. DCM removed fromthe reaction mixture to obtain5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (260 mg).5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml)and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rtfor 1 h. To this mixture added 3-pentanol (46 mg, 0.63 mmol) and TEA(0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up(EtOAc/H₂O) and purification of the crude by combiflash with gradientmixture of ethyl acetate and petether (1:1) as eluent afforded thetitled compound (20 mg) as an off-white solid. M.P.: 114-117° C. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H),7.54-7.50 (m, 1H), 4.69 (quintet, J 6, 1H), 4.23 (d, J 13.5, 2H),3.25-3.15 (m, 1H), 3.07 (t, J 11.9, 2H), 2.21-2.17 (m, 2H), 2.02-1.88(m, 2H), 1.65-1.50 (m, 4H), 0.91 (t, J 7.4, 6H).

Example 265-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole

5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (50 mg) was dissolved in DCM (15 ml) and addedTEA (0.3 ml). This mixture stirred for 3 h at rt. Work up (DCM/H₂O)followed by purification of the crude by preparative TLC using MeOH andDCM (1:5) as eluent afforded the titled compound (15 mg) as an off-whitesolid. M.P.: 148-151° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.17 (s,1H), 8.03 (d, J 9.6, 1H), 7.95-7.79 (m, 4H), 7.58 (d, J 8.5, 1H),3.22-3.13 (m, 1H), 3.07 (d, J 12.4, 2H), 2.70 (t, J 11.2, 2H), 2.06 (d,J 11.1, 2H), 1.82-1.70 (m, 2H).

Example 27 Isopropyl4-{5-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (100 mg) wasprepared from Intermediate 13 (200 mg, 0.54 mmol) and4-(trifluoromethyl)phenylboronic acid (124 mg, 0.65 mmol) as anoff-white solid. M.P.: 123-126° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.88(d, J 1, 1H), 7.72-7.68 (m, 4H), 7.60-7.53 (m, 2H), 4.95 (septet, J 6.3,1H), 4.20 (d, J 13.3, 2H), 3.22-3.12 (m, 1H), 3.04 (t, J 11.3, 2H), 2.17(dd, J 2.6, 13.2, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).

Example 28 Isopropyl4-[5-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (100 mg) wasprepared from Intermediate 13 (270 mg, 0.73 mmol) and4-formylphenylboronic acid (132 mg, 0.88 mmol) as an off-white solid.M.P.: 167-170° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 10.07 (S, 1H), 7.96(dd, J 1.7, 6.6, 2H), 7.93 (s, 1H), 7.76 (d, J 8.2, 2H), 7.58 (s, 2H),4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.1, 2H), 3.22-3.13 (m, 1H), 3.04(t, J 11.3, 2H), 2.18 (dd, J 2.8, 13.3, 2H).

Example 29 Isopropyl4-{5-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Isopropyl4-[5-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (100mg, 0.25 mmol) dissolved in DCM and added DAST (123 mg, 0.76 mmol) andstirred the reaction mixture at 55° C. Work up (DCM/H₂O) followed bypurification on combiflash with a gradient mixture of EtOAc and Petether(1:4) as eluent afforded the titled compound (35 mg) as an off-whitesolid. M. P.: 151-154° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.88 (s, 1H),7.68 (d, J 8.2, 2H), 7.60 (d, J 8.2, 2H), 7.58-7.52 (m, 2H), 6.70 (t, J56.5, 1H), 4.95 (septet, J 6.2, 1H), 4.19 (d, J 11.1, 2H), 3.21-3.13 (m,1H), 3.04 (t, J 11.4, 2H), 2.17 (d, J 10.4, 2H), 2.00-1.88 (m, 2H), 1.26(d, J 6.2, 6H).

Example 30 Isopropyl4-[5-(4-carbamoyl-3-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-2, the titled compound (30 mg) wasprepared from Intermediate 13 (150 mg, 0.41 mmol) and2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (110mg, 0.41 mmol) as a pale-yellow solid. M.P.: 178-181° C. ¹H-NMR (6 ppm,DMSO-d₆, 400 MHz): 8.04 (d, J 1.7, 1H), 7.88 (bs, 1H), 7.80 (d, J 1.7,1H), 7.77 (d, J 8.5, 1H), 7.73-7.68 (m, 2H), 7.62-7.58 (m, 1H), 7.52 (d,J 8, 1H), 4.78 (septet, J 6.2, 1H), 3.97 (d, J 13.2, 2H), 3.34-3.24 (m,1H), 3.10-3.00 (m, 2H), 2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H), 1.19 (d, J6.2, 6H).

Example 31 Isopropyl4-[5-(4-carbamoyl-3-fluorohenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-2, the titled compound (30 mg) wasprepared from Intermediate 14 (300 mg, 0.72 mmol) and4-bromo-2-fluorobenzamide (157 mg, 0.72 mmol) as an off-white solid.M.P.: 184-187° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.08 (d, J 1.4, 1H),7.80-7.72 (m, 3H), 7.70-7.62 (m, 4H), 4.78 (septet, 6.2, 1H), 3.97 (d, J13.4, 2H), 3.33-3.25 (m, 1H), 3.10-2.98 (m, 2H), 2.15-2.07 (m, 2H),1.76-1.64 (m, 2H), 1.19 (d, J 6.2, 6H).

Example 321-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)benzo[d]oxazol-2-yl]piperidin-1-yl}-2-methylpropan-1-one

Tert-butyl4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate(100 mg, 0.22 mmol) dissolved in DCM (25 ml) and added trifluoroaceticacid (0.4 ml). This mixture stirred at rt for 3 h. After completion ofthe reaction, DCM removed on rotavapour and residue was co-distilledwith ether to obtain5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (100 mg).5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (100 mg, 0.21 mmol) was dissolved in DMF (3 ml)and added isobutyric acid (202 mg, 0.23 mmol), EDC.HCl (99 mg, 0.52mmol), HOBt (33 mg, 0.25 mmol) and TEA (0.23 ml, 1.7 mmol). Aftercompletion of the reaction, work up (EtOAc/H₂O) followed by purificationon combiflash using the gradient mixture of EtOAc and Petether (65:35)as eluent afforded the titled compound (20 mg) as a brown solid. M.P.:190-194° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H),7.68 (t, J 8.2, 1H), 7.67-7.59 (m, 2H), 7.52 (td, J 1.6, 8.4, 1H), 4.58(d, J 12.1, 1H), 4.04 (d, J 13.2, 1H), 3.35-3.22 (m, 2H), 2.96 (t, J 12,1H), 2.85 (septet, J 6.8, 1H), 2.30-2.18 (m, 2H), 2.05-1.72 (m, 2H),1.16 (d, J 6.8, 6H).

Example 33 Isopropyl4-{6-[4-(difluoromethyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, Isopropyl4-[6-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (140mg) was prepared from Intermediate 15 (300 mg, 0.82 mmol) and4-formylphenylboronic acid (146 mg, 0.98 mmol) as an off-white solid.Isopropyl4-[6-(4-formylphenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (100mg, 0.25 mmol) was dissolved in DCM (5 ml) and added DAST (0.1 ml, 0.76mmol). This mixture stirred at reflux for 2 h. Work up (DCM/H₂O)followed by the purification of the crude on combiflash using gradientmixture of EtOAc and Petether (1:4) as eluent afforded the titledcompound (35 mg) as an off-white solid. M. P.: 149-153° C. MS (m/z):415.1 [M+H]⁺.

Example 346-{2-[1-(isopropoxycarbonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}nicotinicacid

Following the General Procedure-2, Methyl6-{2-(1-(isopropoxycarbonyl)piperidin-4-yl)benzo[d]oxazol-5-yl]nicotinate(50 mg) was prepared from Intermediate 14 (400 mg, 0.97 mmol) and methyl6-chloronicotinate (166 mg, 0.97 mmol) as a brown solid. Methyl6-{2-(1-(isopropoxycarbonyl)piperidin-4-yl)benzo[d]oxazol-5-yl]nicotinate(35 mg, 0.08 mmol) was dissolved in MeOH (5 ml) and added K₂CO₃ (22 mg,0.17 mmol). This mixture was stirred at reflux for overnight. MeOHremoved on rotavapour and pH adjusted to 6 using acetic acid to obtain asolid. Solid was filtered and dried to obtain the titled compound (20mg) as a grey solid. M. P.: 239-242° C. MS (m/z): 410.4 [M+H]⁺

Example 355-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(methylsulfonyl)piperidin-4-yl]benzo[d]oxazole

5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DCM (5 ml)and added TEA (60 mg, 0.6 mmol) and stirred the mixture at rt for 30mins. To this mixture added methanesulphonyl chloride (14 mg, 0.12 mmol)and stirred at rt for 2 h. Work up (DCM/H₂O) followed by purification oncombiflash using a gradient mixture of EtOAc and Petether (7:3) aseluent afforded the titled compound (17 mg) as a brown solid. M. P.:209-212° C. MS (m/z): 443.2 [M+H]⁺.

Example 36 Isopropyl4-[5-(5-carbamoylpyridin-2-yl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (40 mg) wasprepared from Intermediate 14 (250 mg, 0.6 mmol) and6-chloronicotinamide (94 mg, 0.6 mmol) as an off-white solid. M.P.:227-230° C. MS (m/z): 409.1 [M+H]⁺.

Example 37 Isopropyl4-[5-(4-carbamoyl-2-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (80 mg) wasprepared from Intermediate 14 (200 mg, 0.48 mmol) and4-bromo-3-fluorobenzamide (105 mg, 0.48 mmol) as an off-white solid.M.P.: 194-197° C. MS (m/z): 426.0 [M+H]⁺.

Example 38 Isopropyl4-[5-(4-carbamoyl-2-chlorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (80 mg) wasprepared from Intermediate 14 (200 mg, 0.48 mmol) and4-bromo-3-chlorobenzamide (105 mg, 0.48 mmol) as a brown solid. M.P.:178-182° C. MS (m/z): 442.0 [M+H]⁺.

Example 392-Fluoro-4-{2-[1-(3-methylbutanoyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide

Tert-butyl4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate(140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added trifluoroaceticacid (1 ml). This mixture stirred at rt for 3 h. After completion of thereaction, DCM removed on rotavapour and residue was co-distilled withether to obtain2-fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide2,2,2-trifluoroacetate (140 mg).2-Fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide2,2,2-trifluoroacetate (140 mg, 0.31 mmol) was dissolved in DMF (5 ml)and added isovaleric acid (34.6 mg, 0.34 mmol), EDC.HCl (147 mg, 0.77mmol), HOBt (50 mg, 0.37 mmol) and TEA (0.4 ml, 2.47 mmol). Aftercompletion of the reaction, water added to the reaction mixture toobtain solid. Solid was filtered and washed with ether to obtain thetitled compound (20 mg) as a brown solid. M.P.: 186-190° C. MS (m/z):424.1 [M+H]⁺.

Example 401-{4-[5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl]piperidin-1-yl}-3-methylbutan-1-one

5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (140 mg, 0.29 mmol) was dissolved in DMF (4 ml)and added isovaleric acid (38 mg, 0.37 mmol), EDC.HCl (147 mg, 0.73mmol), HOBt (47 mg, 0.35 mmol) and TEA (88 mg, 0.88 mmol). Aftercompletion of the reaction, work up (EtOAc/H₂O) followed by purificationof crude on combiflash using a gradient mixture of EtOAc and Petether(7:3) as eluent afforded the titled compound (100 mg) as a pale-yellowsolid. M.P.: 168-172° C. MS (m/z): 449.1 [M+H]⁺

Example 415-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-[1-(2-methoxyethyl)piperidin-4-yl]benzo[d]oxazole

5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DMF (2 ml)and added K₂CO₃ (40 mg, 0.29 mmol) and stirred the mixture at rt for 15mins. To this mixture added 2-methoxyethyl methanesulfonate (45 mg, 0.29mmol) and stirred at rt for 17 h. Work up (EtOAc/H₂O) followed bypurification by column chromatography on 60-120 mesh silicagel using agradient mixture of DCM and MeOH (98:2) as eluent afforded the titledcompound (90 mg) as a brown solid (15 mg). M.P.: 148-152° C. MS (m/z):423.3 [M+H]⁺.

Example 42 Isopropyl4-{5-[3-fluoro-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (80 mg) wasprepared from Intermediate 14 (200 mg, 0.54 mmol) and4-bromo-2-fluoro-N-methylbenzamide (200 mg, 0.54 mmol) as a brown solid.M.P.: 116-120° C. MS (m/z): 440.3 [M+H]⁺.

Example 432-Fluoro-4-[2-(1-isobutyrylpiperidin-4-yl)benzo[d]oxazol-5-yl]benzamide

Tert-butyl4-[5-(4-carbamoyl-3-flurophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate(190 mg, 0.32 mmol) dissolved in DCM (40 ml) and added trifluoroaceticacid (1.5 ml). This mixture stirred at rt for 3 h. After completion ofthe reaction, DCM removed on rotavapour and residue was co-distilledwith ether to obtain2-fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide2,2,2-trifluoroacetate (190 mg).2-Fluoro-4-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzamide2,2,2-trifluoroacetate (190 mg, 0.42 mmol) was dissolved in DMF (7 ml)and added isobutyric acid (47 mg, 0.46 mmol), EDC.HCl (200 mg, 1.04mmol), HOBt (70 mg, 0.5 mmol) and TEA (0.7 ml, 3.3 mmol). Aftercompletion of the reaction, water added to the reaction mixture toobtain solid. Solid was filtered and washed with ether to obtain thetitled compound (120 mg) as a brown solid. M.P.: 193-196° C. MS (m/z):410.2 [M+f1]⁺

Example 44 Isopropyl4-[6-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (55 mg) wasprepared from Intermediate 16 (360 mg, 0.87 mmol) and4-bromo-2-fluorobenzamide (190 mg, 0.87 mmol) as an off-white solid.M.P.: 178-181° C. MS (m/z): 425.45 [M+H]⁺.

Example 45 Isopropyl4-{5-[3-fluoro-4-(2-hydroxyethylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (65 mg) wasprepared from Intermediate 14 (200 mg, 0.54 mmol) and4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (110 mg, 0.43 mmol) as abrown solid. M.P.: 145-147° C. MS (m/z): 470.4 [M+H]⁺.

Example 46 Isopropyl4-{5-[3-fluoro-4-(isopropylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (45 mg) wasprepared from Intermediate 13 (200 mg, 0.54 mmol) and3-fluoro-4-(isopropylcarbamoyl)phenylboronic acid (120 mg, 0.54 mmol) asa grey solid. M.P.: 147-150° C. MS (m/z): 468.4 [M+H]⁺.

Example 47 Isopropyl4-{5-[4-(N-methylsulfamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (35 mg) wasprepared from Intermediate 13 (200 mg, 0.54 mmol) and4-(N-methylsulfamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a whitesolid. M.P.: 179-181° C. MS (m/z): 458.3 [M+H]⁺

Example 48 Isopropyl4-{5-[6-(methylcarbamoyl)pyridin-3-yl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-1, the titled compound (20 mg) wasprepared from Intermediate 13 (300 mg, 0.82 mmol) andN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(256 mg, 0.98 mmol) as a brown solid. M.P.: 158-161° C. MS (m/z): 423.5[M+H]⁺

Example 49 Isopropyl4-{5-[3-methyl-4-(methylcarbamoyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (30 mg) wasprepared from Intermediate 13 (250 mg, 0.68 mmol) andN,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(187 mg, 0.68 mmol) as an off-white solid. M.P.: 151-154° C. MS (m/z):436.5 [M+H]⁺

Example 50 Isopropyl4-{5-[4-(cyclopropylcarbamoyl)-3-fluorophenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate

Following the General Procedure-3, the titled compound (20 mg) wasprepared from Intermediate 14 (250 mg, 0.61 mmol) and4-bromo-N-cyclopropyl-2-fluorobenzamide (156 mg, 0.61 mmol) as anoff-white solid. M.P.: 162-165° C. MS (m/z): 466.3 [M+H]⁺

Example 512-Fluoro-4-{2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide

Following general procedure-3 and using DMF as solvent titled compound(40 mg) was obtained from intermediate 19 (150 mg, 0.35 mmol) and4-bromo-2-fluorobenzamide (77 mg, 0.35 mmol) as a brown solid. M.P.:226-229° C. MS (m/z): 436.5 [M+H]⁺

Example 52 Tert-butyl4-[5-(4-carbamoyl-3-fluorophenyl)benzofuran-2-yl]-5,6-dihydropyridine-1(2H)-carboxylate

Following the general procedure-4, the titled compound (370 mg) wasobtained from intermediate 21 (1.5 g, 5.02 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(1.99 g, 6 mmol) as a white solid. M.P.: 189-191° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 7.95 (s, 1H), 7.77-7.71 (m, 1H), 7.69-7.58 (m, 6H),6.91 (s, 1H), 6.50 (s, 1H), 4.10-4.05 (m, 2H), 3.56 (t, J 5.5, 2H),3.30-3.20 (m, 2H), 1.42 (s, 9H).

Example 532-fluoro-4-{2-[1-(propylsulfonyl)piperidin-4-yl]benzo[d]oxazol-5-yl}benzamide

Intermediate 25 (80 mg, 0.24 mmol) was dissolved in DCM (10 ml) andadded TEA (35 mg, 0.35 mmol). This mixture was stirred at rt for 15 minsReaction mixture cooled to 0° C. and added propane-1-sulphonylchloride(33 mg, 0.23 mmol). Reaction mixture stirred at rt for 2 h. Work up(DCM/H₂O) afforded the crude product. Crude was purified by columnchromatography on 60-120 mesh silica gel using a gradient mixture ofEtOAC and Petether (70:30) as eluent to afford the titled compound (8mg) as a white solid. M.P.: 222-225° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.09 (d, J 1.3, 1H), 7.82-7.72 (m, 3H), 7.71-7.61 (m, 4H),3.67-3.58 (m, 2H), 3.30-3.22 (m, 2H), 3.09-2.99 (m, 2H), 2.25-2.16 (m,2H), 1.92-1.79 (m, 2H), 1.69 (hextet, J 7.6, 2H), 0.98 (t, J 7.4, 3H).

Example 56 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate

2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (880 mg, 2.12 mmol), tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(700 mg, 2.12 mmol) and sodium carbonate (1.13 g, 11.48 mmol) weredissolved in DMF (20 ml) under N₂ atmosphere. This mixture was degassedwith nitrogen for 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (138 mg, 0.17mmol). This mixture stirred at 80° C. for 90 mins in microwave. Reactionmixture diluted with water and work up (AcOEt/H₂O) afforded the crude.Crude was purified by combiflash using a mixture of AcOEt and Petether(35:65) to afford the titled compound (240 mg) as an off-white solid.¹H-NMR (6 ppm, DMSO-d₆, 400 MHz): 12.80 (s, 1H), 8.49 (t, J 7.5, 1H),8.02 (d, J 10.4, 1H), 7.92 (d, J 8.2, 1H), 7.88-7.67 (m, 1H), 7.66-7.54(m, 1H), 7.48-7.39 (m, 1H), 6.18 (bs, 1H), 4.02 (bs, 2H), 3.57 (bs, 2H),3.34 (s, 3H), 2.60-2.55 (m, 2H), 1.43 (s, 9H).

Example 57 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}piperidine-1-carboxylate

Example 56 (240 mg, 0.51 mmol) was dissolved in MeOH (25 ml) and added10% Pd/C (100 mg). This mixture was stirred in an auto clave underhydrogen atmosphere at 55 psi for 14 h. After 14 h, reaction massfiltered through a pad of celite and celite washed thoroughly withmethanol. Methanol removed on rotavapour to obtain the titled compound(200 mg) as an off-white solid. M.P.: 208-211.5° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 12.71 (s, 1H), 8.47 (t, J 7.7, 1H), 8.01 (d, J 10.4,1H), 7.91 (dd, J 1.4, 8.2, 1H), 7.65-7.40 (m, 2H), 7.30-7.24 (m, 1H),4.08 (d, J 11.1, 2H), 3.33 (s, 3H), 2.92-2.74 (m, 3H), 1.81 (d, J 12.2,2H), 1.54 (d, J 10.4, 2H), 1.42 (s, 9H).

Example 585-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole

Example 57 (150 mg, 0.3 mmol) dissolved in DCM (12 ml) and added TFA(0.45 ml). This mixture stirred at rt for 3 h. After 3 h, DCM removed onrotavapour and co-distilled with DCM to obtain2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)-1H-benzo[d]imidazole2,2,2-trifluoroacetate (150 mg).2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)-1H-benzo[d]imidazole2,2,2-trifluoroacetate (150 mg, 0.4 mmol) and 2-chloro-5-ethylpyrimidine(60 mg, 0.4 mmol) were dissolved in propan-2-ol (10 ml) and added DiPEA(0.6 ml, 3.2 mmol). This mixture was refluxed at 90° C. for 12 h. After12 h, propan-2-ol removed on rotavapor to obtain the residue. Residuewas purified on combiflash using Ethyl acetate and Petether (1:1) aseluent to afford the titled compound (50 mg) as a white solid. M.P.:220-223.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.69 (d, J 12.8, 1H),8.49-8.45 (m, 1H), 8.24 (s, 2H), 8.00 (dd, J 1.5, 10.4, 1H), 7.91 (d, J8.3, 1H), 7.67-7.56 (m, 1H), 7.55-7.40 (m, 1H), 7.22-7.12 (m, 1H), 4.80(d, J 12.6, 2H), 3.33 (s, 3H), 2.97-2.91 (m, 3H), 2.43 (q, J 7.5, 2H),1.89 (d, J 12.4, 2H), 1.69-1.54 (m, 2H), 1.13 (t, J 7.6, 3H).

Example 59 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate

2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (50 mg, 0.12 mmol), tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (39mg, 0.12 mmol) and sodium carbonate (38 mg, 0.36 mmol) were dissolved inDMF (2 ml) under N₂ atmosphere. This mixture was degassed with nitrogenfor 30 mins and added Pd(dppf)₂Cl₂.CH₂Cl₂ (10 mg, 0.009 mmol). Thismixture stirred at 80° C. for 90 mins in microwave. Reaction mixturediluted with water and work up (AcOEt/H₂O) afforded the crude. Crude waspurified by combiflash using a mixture of AcOEt and Petether (27:73) toafford the titled compound (25 mg) as an off-white solid. M.P.: 149-151°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.47 (t, J 7.4, 1H), 7.93-7.80 (m,3H), 7.65-7.57 (m, 1H), 7.53-7.45 (m, 1H), 6.20-6.02 (m, 1H), 4.12 (bs,2H), 3.68 (t, J 5.3, 2H), 3.13 (s, 3H), 2.65-2.55 (m, 2H), 1.50 (s, 9H).

Example 60 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

Example 59 (300 mg, 0.64 mmol) was dissolved in MeOH (25 ml) and added10% Pd/C (100 mg). This mixture was stirred in an auto clave underhydrogen atmosphere at 55 psi for 14 h. After 14 h, reaction massfiltered through a pad of celite and celite washed thoroughly withmethanol. Methanol removed on rotavapour to obtain the titled compound(200 mg) as an off-white solid. M.P.: 168-171° C. ¹H-NMR (δ ppm, CDCl₃,400 MHz): 8.46 (t, J 7.1, 1H), 7.87 (t, J 7.6, 2H), 7.69 (s, 1H), 7.57(d, J 8.4, 1H), 7.30 (d, J 7.7, 1H), 4.35-4.20 (m, 2H), 3.13 (s, 3H),2.90-2.75 (m, 3H), 1.90 (d, J 12.6, 2H), 1.63-1.74 (m, 2H), 1.49 (s,9H).

Example 612-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate

Example 60 (170 mg, 0.36 mmol) dissolved in DCM (15 ml) and added TFA(0.6 ml). This mixture stirred at rt for 3 h. After 3 h, DCM removed onrotavapour and co-distilled with DCM to obtain2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (180 mg). M.P.: 223-227° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.61 (bs, 1H), 8.47 (t, J 7.6, 1H), 8.39 (bs, 1H),8.07 (d, J 10, 1H), 7.98 (d, J 8.1, 1H), 7.83 (d, J 8.4, 1H), 7.74 (s,1H), 7.39 (d, J 8.3, 1H), 3.45-3.33 (m, 5H), 3.10-2.98 (m, 3H), 2.02 (d,J 12.9, 2H), 1.93-1.80 (m, 2H).

Example 625-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole

Example 61 (150 mg, 0.31 mmol) and 2-chloro-5-ethylpyrimidine (48 mg,0.34 mmol) were dissolved in propan-2-ol (20 ml) and added DiPEA (0.4ml, 2.45 mmol). This mixture was refluxed at 90° C. for 12 h. After 12h, propan-2-ol removed on rotavapor to obtain the residue. Residue waspurified on combiflash using Ethyl acetate and Petether (35:65) aseluent to afford the titled compound (30 mg) as a white solid. M.P.:190-194° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.49-8.43 (m, 1H), 8.20 (s,2H), 7.90-7.84 (m, 2H), 7.71 (s, 1H), 7.57 (d, J 8.4, 1H), 7.33 (d, J7.6, 1H), 4.91 (d, J 13.3, 2H), 3.13 (s, 3H), 3.05-2.90 (m, 3H), 2.48(q, J 7.5, 2H), 2.00 (d, J 13, 2H), 1.83-1.70 (m, 2H), 1.20 (t, J 7.6,3H).

Example 63 Tert-butyl4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

Following the general procedure-1 Tert-butyl4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate(180 mg) obtained from intermediate 31 (600 mg, 1.38 mmol) andtert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(456 mg, 1.38 mmol). Tert-butyl4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate(150 mg, 0.30 mmol) dissolved in MeOH and added Pd/C (71 mg). Thismixture was stirred in an auto clave in hydrogen atmosphere at 55 Psifor 12 h. Reaction mixture filtered through celite and washed the cetilewith MeOH. Methanol was removed on rotavapour to obtain the titledcompound (100 mg) as a brown solid. M.P.: 188-192.4° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.47 (t, J 7.12, 1H), 7.89 (t, J 7.6, 2H), 7.49 (s,1H), 7.07 (d, J 11.2, 1H), 4.28 (bs, 2H), 3.13 (s, 3H), 2.90-2.72 (m,3H), 1.95-1.85 (m, 2H), 1.72-1.56 (m, 2H). 1.49 (s, 9H).

Example 64 Isopropyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

Example 61 (100 mg, 0.20 mmol) was dissolved in DCM (10 ml) and addedTEA (1.4 ml). This mixture was stirred at rt for 30 mins Isopropylchloroformate in toluene (50 mg, 0.41 mmol) added to the above mixtureand stirred at rt for 1 h. Reaction mixture diluted with water andextracted with DCM. DCM removed on rotavapour to obtain the crude. Crudewas purified by combiflash with EA and Petehter (35:65) as eluent toafford the title compound (50 mg) as an off-white solid. M.P.:151.4-156.5° C. ¹H-NMR (δ ppm DMSO-d₆, 400 MHz): 8.47 (t, J 7.8, 1H),8.05 (d, J 10.3, 1H), 7.97 (dd, J 1.5, 8.2, 1H), 7.78-7.74 (m, 2H), 7.42(d, J 8.6, 1H), 4.79 (heptet, J 6.2, 1H), 4.12 (d, J 11.6, 2H), 3.29 (s,3H), 2.95-2.80 (m, 3H), 1.86-1.77 (m, 2H), 1.65-1.55 (m, 2H), 1.20 (d, J6.2, 6H).

Example 65 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate

Following the general procedure-1, the titled compound (140 mg) wasobtained from intermediate 35 (300 mg, 0.69 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(230 mg, 0.69 mmol) as a brown solid. M.P.: 159.9-163.5° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.68 (t, J 6.9, 1H), 8.09 (d, J 8.6, 1H), 7.94 (d,J 1.3, 1H), 7.90-7.82 (m, 2H), 7.88 (d, J 1.7, 8.2, 1H), 6.18 (s, 1H),4.13 (d, J 2.3, 2H), 3.69 (t, J 5.6, 2H), 3.12 (s, 3H), 2.62 (bs, 2H),1.50 (s, 9H).

Example 66 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate

Following the general procedure-1, the titled compound (120 mg) wasobtained from intermediate 39 (230 mg, 0.53 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(175 mg, 0.53 mmol) as an yellow solid. M.P.: 170-174.8° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.71-8.67 (m, 1H), 8.13 (d, J 1.3, 1H), 7.95-7.82(m, 3H), 7.55 (dd, J 1.7, 8.5, 1H), 6.19 (s, 1H), 4.14 (d, J 2.6, 2H),3.70 (t, J 5.6, 2H), 3.12 (s, 3H), 2.70-2.60 (m, 2H), 1.51 (s, 9H).

Example 67 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate

Following the general procedure-1 Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate(35 mg) obtained from intermediate 41 (400 mg, 0.96 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(318 mg, 0.961 mmol). Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate(50 mg, 0.11 mmol) dissolved in MeOH and added Pd/C (30 mg). Thismixture was stirred in an auto clave under hydrogen atmosphere at 55 Psifor 12 h. Reaction mixture filtered through celite and washed the cetilewith MeOH. Methanol was removed on rotavapour to obtain the crude. Crudewas purified by combiflash using EtOAc and Petether (38:62) as eluent toobtain titled compound (18 mg) as an off-white solid. M.P.: 166.2-169.3°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.48-8.46 (m, 1H), 7.91-7.83 (m, 2H),7.78 (d, J 8.3, 1H), 7.49 (s, 1H), 7.33-7.25 (m, 1H), 4.35-4.20 (m, 2H),3.13 (s, 3H), 2.90-2.75 (m, 3H), 1.95-1.85 (m, 2H), 1.75-1.60 (m, 2H),1.49 (s, 9H).

Example 68{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate

Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate(30 mg, 0.06 mmol) dissolved in MeOH and added Pd/C (30 mg). Thismixture was stirred in an auto clave under hydrogen atmosphere at 55 Psifor 87 h. Reaction mixture filtered through celite and washed the cetilewith MeOH. Methanol was removed on rotavapour to obtain the crude. Crudewas purified by combiflash using EtOAc and Petether (20:80) as eluent toobtain titled compound (12 mg) as a pale-yellow solid. M.P.:173.3-178.1° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.71-8.65 (m, 1H), 7.99(s, 1H), 7.93-7.82 (m, 3H), 7.35 (dd, J 1.5, 8.3, 1H), 4.35-4.20 (m,2H), 3.12 (s, 3H), 2.91-2.79 (m, 3H), 1.96-1.88 (m, 2H), 1.80-1.68 (m,2H), 1.50 (s, 9H).

Example 69 Ethyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (80 mg, 0.16 mmol) dissolved in DCM (10 ml) andadded TEA (0.12 ml, 0.8 mmol). This mixture was stirred at rt for 30mins Ethylchloro formate (35 mg, 0.33 mmol) was added to the abovemixture and stirred at rt for 30 mins Reaction mixture extracted withDCM. DCM removed on rotavapour to obtain the crude. Crude was purifiedby combiflash using EtOAc and Petether (38:62) as eluent to afford thetitled compound (20 mg) as an off-white solid. M.P.: 145-148° C. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): 8.49-8.44 (m, 1H), 7.90-7.84 (m, 2H), 7.69 (d,J 1.2, 1H), 7.58 (d, J 8.5, 1H), 7.30 (dd, J 1.6, 8.5, 1H), 4.40-4.28(m, 2H), 4.17 (q, J 7.1, 2H), 3.13 (s, 3H), 2.95-2.79 (m, 3H), 1.96-1.88(m, 2H), 1.75-1.65 (m, 2H), 1.29 (t, J 7.1, 3H).

Example 70 Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

Following the general procedure-1, Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate(90 mg) obtained from intermediate 44 (200 mg, 0.51 mmol) and Tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(170 mg, 0.511 mmol). Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate(90 mg, 0.2 mmol) dissolved in MeOH (30 ml) and added Pd/C (90 mg). Thismixture was stirred in an auto clave in hydrogen atmosphere at 55 Psifor 12 h. Reaction mixture filtered through celite and washed the cetilewith MeOH. Methanol was removed on rotavapour to obtain the crude. Crudewas triturated with Petether and EtOAc (1:1) to obtain the titledcompound (50 mg) as an off-white solid. M.P.: 161-164° C. ¹H-NMR (δ ppmCDCl₃, 400 MHz): 8.36 (d, J 8.2, 2H), 7.78 (d, J 8.4, 2H), 7.63 (d, J1.5, 1H), 7.53 (d, J 8.4, 1H), 7.26-7.20 (m, 1H), 4.34-4.20 (m, 2H),2.90-2.75 (m, 3H), 1.93-1.84 (m, 2H), 1.74-1.62 (m, 2H), 1.49 (s, 9H).

Example 71 Isopropyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate

Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate(270 mg, 5.7 mmol) dissolved in THF (5 ml) and added Et₂O.HCl (10 ml).Reaction mixture stirred at rt for 3 h. Ether removed on rotavapour toobtain crude. Crude was triturated with ether to obtain2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]oxazolehydrochloride (225 mg).2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]oxazolehydrochloride (70 mg, 0.17 mmol) was dissolved in DCM (5 ml) and addedTEA (0.11 ml, 0.85 mmol). This mixture stirred at rt for 30 mins andadded isopropylchloro formate in toluene (42 mg, 0.34 mmol). After 30mins reaction mixture quenched with water and extracted with DCM. DCMremoved on rotavapour to obtain the crude. Crude was purified bycombiflash using EtOAC and Petether (1:3) as eluent to afford the titledcompound (30 mg) as a white solid. M.P.: 170.3-174.3° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.47-8.44 (m, 1H), 7.90-7.83 (m, 2H), 7.78 (d, J 8.3,1H), 7.49 (s, 1H), 7.28 (dd. J 1.5, 8.3, 1H), 4.96 (septet, J 6.2, 1H),4.40-4.28 (m, 2H), 3.13 (s, 3H), 2.92-2.80 (m, 3H), 1.96-1.88 (m, 2H),1.75-1.62 (m, 2H), 1.28 (d, J 6.2, 6H).

Example 72 Ethyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate

2-[2-fluoro-4-(methyl sulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]oxazolehydrochloride (70 mg, 0.17 mmol) from Example 71 was dissolved in DCM(10 ml) and added TEA (0.12 ml, 0.83 mmol). This mixture stirred at rtfor 30 mins and added Ethylchloro formate (35 mg, 0.34 mmol). After 30mins reaction mixture quenched with water and extracted with DCM. DCMremoved on rotavapour to obtain the crude. Crude was purified bycombiflash using EtOAc and Petether (1:3) as eluent to afford the titledcompound (30 mg) as a white solid. M.P.: 153.5-157.5° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.49-8.43 (m, 1H), 7.90-7.82 (m, 2H), 7.78 (d, J 8.3,1H), 7.49 (s, 1H), 7.28 (dd, J 1.4, 8.3, 1H), 4.42-4.28 (m, 2H), 4.17(q, J 7.1, 2H), 3.13 (s, 3H), 2.95-2.80 (m, 3H), 1.96-1.88 (m, 2H),1.75-1.65 (m, 2H), 1.29 (t, J 7.1, 3H).

Example 73 Ethyl4-{2-[2-fluoro-4-(methylsulfonyhenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate

Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate(130 mg, 0.27 mmol) dissolved in DCM (5 ml) and added TFA (0.5 ml).Reaction mixture stirred at rt for 3 h. DCM removed on rotavapour toobtain crude. Crude was triturated with ether to obtain2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]thiazole2,2,2-trifluoroacetate (150 mg). 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]thiazole 2,2,2-trifluoroacetate (105mg, 0.21 mmol) was dissolved in DCM (20 ml) and added TEA (0.23 ml, 1.66mmol). This mixture stirred at rt for 30 mins and added isopropylchloroformate in toluene (51 mg, 0.42 mmol). After 30 mins reaction mixturequenched with water and extracted with DCM. DCM removed on rotavapour toobtain the crude. Crude was purified by combiflash using EtOAc andPetether (1:3) as eluent to afford the titled compound (60 mg) as a greysolid. M.P.: 174-177° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.71-8.65 (m,1H), 8.00 (d, J 1.2, 1H), 7.93-7.81 (m, 3H), 7.35 (dd, J 1.6, 8.4, 1H),4.96 (septet, J 6.2, 1H), 4.40-4.22 (m, 2H), 3.12 (s, 3H), 2.95-2.82 (m,3H), 2.0-1.90 (m, 2H), 1.80-1.64 (m, 2H), 1.28 (d, J 6.3, 6 H).

Example 74 Benzyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (Example 61) (70 mg, 0.14 mmol) dissolved in DCM(10 ml) and added TEA (0.1 ml, 0.72 mmol). This mixture stirred at rtfor 30 mins and added benzyl carbonochloridate in toluene (48 mg, 0.28mmol). After 30 mins reaction mixture quenched with water and extractedwith DCM. DCM removed on rotavapour to obtain the crude. Crude waspurified by combiflash using EtOAc and Petether (1:2) as eluent toafford the titled compound (30 mg) as an off-white solid. M.P.: 172-175°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.49-8.43 (m, 1H), 7.90-7.84 (m, 2H),7.68 (d, J 1.4, 1H), 7.57 (d, J 8.5, 1H), 7.42-7.22 (m, 6H), 5.17 (s,2H), 4.42-4.25 (bs, 2H), 3.13 (s, 3H), 3.00-2.78 (m, 3H), 2.00-1.88 (m,2H), 1.80-1.65 (m, 2H).

Example 75 Isobutyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (Example 61) (140 mg, 0.29 mmol), isobutanol (42mg, 0.58 mmol), N,N-Carbonyl diimidazole (82 mg, 0.50 mmol) and TEA (0.2ml, 1.26 mmol) were dissolved in DMF (2.4 ml). Reaction mixture heatedto 60° C. for 18 h. Work up (EtOAc/H₂O) followed by purification of thecrude by column chromatography on 60-120 mesh silica gel using EtOAc andPetether as eluent to afford the titled compound as a white solid. M.P.:169-173° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.49-8.43 (m, 1H), 7.83-7.90(m, 2H), 7.69 (d, J 1.4, 1H), 7.58 (d, J 8.5, 1H), 7.30 (dd, J 1.7, 8.5,1H) 4.42-4.26 (m, 2H), 3.90 (d, J 6.7, 2H), 3.13 (s, 3H), 3.00-2.78 (m,3H), 2.00-1.88 (m, 3H), 1.80-1.65 (m, 2H), 0.96 (d, J 6.7, 6H).

Example 76 Isopropyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-6-yl}piperidine-1-carboxylate

Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate(190 mg, 0.38 mmol) dissolved in DCM, cooled to 0° C., trifluoroaceticacid (0.8 ml) was added and stirred the reaction mixture at rt for 3 h.DCM and trifluoroacetic acid was removed on rotavapour to obtain thecrude. Crude was washed with petether to obtain2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]thiazole(190 mg) as an off-white solid.2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzoldlthiazole(190 mg, 0.38 mmol) dissolved in DCM (20 ml). To this mixture added TEA(0.3 g, 3 mmol) and stirred the reaction mixture at rt for 30 minsReaction mixture cooled to 0° C. and added isopropylchloro formate (92mg, 0.75 mmol). This mixture was stirred at rt for 30 mins Work up(DCM/H₂O) followed by evaporation of the DCM on rotavapour affordedcrude. Crude was triturated with diethyl ether and dried on high vacuumto afford the titled compound (60 mg) as a white solid. M.P.: 163-166°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):

Example 77 Isopropyl4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}piperidine-1-carboxylate

Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate(80 mg, 0.17 mmol) dissolved in DCM (15 ml), cooled to 0° C.,trifluoroacetic acid (0.1 ml) was added and stirred the reaction mixtureat rt for 3 h. DCM and trifluoroacetic acid was removed on rotavapour toobtain the crude. Crude was washed with petether to obtain5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole2,2,2-trifluoroacetate (90 mg) as an off-white solid.5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole2,2,2-trifluoroacetate (90 mg, 0.19 mmol) dissolved in DCM (15 ml). Tothis mixture added TEA (0.1 ml, 0.56 mmol) and stirred the reactionmixture at rt for 30 mins. Reaction mixture cooled to 0° C. and addedisopropylchloro formate (46 mg, 0.38 mmol). This mixture was stirred atrt for 30 mins Work up (DCM/H₂O) followed by evaporation of the DCM onrotavapour afforded crude. Crude was purified with combiflash using agradient mixture of ethylacetate and petether (15:85) as eluent toafford the titled compound (30 mg) as an off-white solid. M.P.: 145-148°C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.36 (d, J 8.1, 2H), 7.78 (d, J 8.3,2H), 7.62 (d, J 1.5, 1H), 7.54 (d, J 8.5, 1H), 7.29-7.21 (m, 1H), 4.96(septet, 6.2, 1H), 4.31 (bs, 2H), 2.95-2.76 (m, 3H), 1.90 (d, J 12.7,2H), 1.75-1.63 (m, 2H), 1.27 (d, J 6.2, 6H).

Example 78 Isopropyl4-(2-p-tolylbenzobiloxazol-6-yl)piperidine-1-carboxylate

Intermediate 49 (40 mg, 0.14 mmol) was dissolved in DCM (10 ml) andadded trifluooroacetic acid (0.15 ml) at 0° C. This mixture was stirredat rt for 3 h. After 3 h DCM was removed on rotavapour and the residuethat obtained was washed with diethyl ether to obtain6-(piperidin-4-yl)-2-p-tolylbenzo[d]oxazole 2,2,2-trifluoroacetate (40mg). 6-(piperidin-4-yl)-2-p-tolylbenzo[d]oxazole 2,2,2-trifluoroacetate(40 mg, 0.1 mmol) was dissolved in DCM (10 ml) and added TEA (0.1 ml,0.79 mmol) at 0° C. To the above mixture isopropylchloro formate (24 mg,0.2 mmol) was added and stirred at rt for 15 mins. Workup (DCM/H₂O)followed by column purification on 60-120 mesh silica gel using EtOAcand Petether (2:8) as eluent afforded the titled compound (12 mg) as anoff-white solid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.12 (d, J 8.2, 2H),7.66 (d, J 8.2, 1H), 7.40 (d, J 1.2, 1H), 7.32 (d, J 8, 2H), 7.19 (dd, J1.4, 8.2, 1H), 4.96 (septet, J 6.2, 1H), 4.32 (bs, 2H), 2.93-2.75 (m,3H), 2.44 (s, 3H), 1.90 (d, J 13.4, 2H), 1.75-1.65 (m, 2H), 1.27 (d, J6.2, 6H).

Example 793-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]-5,6-dihydropyridin-1(2H)-ylsulfonyl}propan-1-ol

Example 59 (200 mg, 0.42 mmol) was dissolved in DCM (30 ml) and addedTFA (1.5 ml, 9.2 mmol). This mixture was stirred at rt for 3 h and DCMwas removed on rotavapour to obtain a residue. Residue was co-distilledwith diethyl ether to obtain 2-(2-fluoro-4-(methylsulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (210 mg).2-(2-fluoro-4-(methylsulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole2,2,2-trifluoroacetate (200 mg, 0.4 mmol) was dissolved in DCM (10 ml)and added TEA (0.46 ml, 3.3 mmol). This mixture was stirred at rt for 30mins After 30 mins reaction mixture cooled to 0° C. and added ethyl3-(chlorosulfonyl)propanoate (164 mg, 0.4 mmol). This reaction continuedfor 30 mins at rt. Work up (H₂O/DCM) followed by column purification oncombiflash using a gradient mixture of EtOAc and Petether (45:55) aseluent afforded ethyl2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridin-1(2H)-ylsulfonyl)acetate(120 mg). Ethyl2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridin-1(2H)-ylsulfonyl)acetate(100 mg, 0.19 mmol) was dissolved in THF (5 ml) and addedLithiumaluminium hydride (14 mg, 0.38 mmol) at 0° C. This mixture wasstirred at same temperature for 90 mins After completion of thereaction, reaction mass quenched with 1N HCl (7 ml). Work up (DCM/H₂O)followed by purification on combiflash using a gradient mixture of EtOAcand Petether (80:20) as eluent afforded the titled compound (40 mg) as awhite solid. M.P.: 184-186° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.48 (t,J 8.1, 1H), 8.06 (dd, J 1.6, 10.1, 1H), 8.00-7.94 (m, 2H), 7.84 (d, J8.6, 1H), 7.63 (dd, J 1.8, 8.5, 1H), 6.29 (s, 1H), 4.64 (t, J 5.3, 1H),3.94 (d, J 2.9, 2H), 3.50-3.42 (m, 4H), 3.36 (s, 3H), 3.18-3.10 (m, 2H),2.70-2.62 (m, 2H), 1.88-1.80 (m, 2H).

Example 803-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}propan-1-ol

Example 61 (0.2 g, 0.41 mmol) was dissolved in DCM and and added TEA(0.33 g, 3.3 mmol). This mixture was stirred at rt for 30 mins After 30mins reaction mixture cooled to 0° C. and added ethyl3-(chlorosulfonyl)propanoate (245 mg, 1.2 mmol). This reaction continuedfor 30 mins at rt. Work up (H₂O/DCM) followed by column purification oncombiflash using a gradient mixture of EtOAc and Petether (65:35) aseluent afforded ethyl2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}acetate.Ethyl2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}acetate(100 mg, 0.19 mmol) was dissolved in THF (5 ml) and addedLithiumaluminium hydride (14 mg, 0.37 mmol) at 0° C. This mixture wasstirred at same temperature for 90 mins After completion of thereaction, reaction mass quenched with 1N HCl (7 ml). Work up (DCM/H₂O)followed by purification on combiflash using a gradient mixture of EtOAcand Petether (65:35) as eluent afforded the titled compound (120 mg) asan off-white solid. M.P.: 204-206° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):8.47 (t, J 8.03, 1H), 8.06 (dd, J 1.6, 10.1, 1H), 7.97 (dd, J 1.6, 8.2,1H), 7.82-7.75 (m, 2H), 7.43 (dd, J 1.5, 8.6, 1H), 4.66 (t, J 5.3, 1H),3.74 (d, J 12.1, 2H), 3.50 (q, J 6.1, 2H), 3.38 (s, 3H), 3.12-3.06 (m,2H), 2.98-2.80 (m, 3H), 1.96-1.90 (m, 2H), 1.88-1.81 (m, 2H), 1.79-1.69(m, 2H).

Example 813-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}propan-1-ol

Example 61 (150 mg, and 0.31 mmol) and 2-Chloro-5-fluoropyrimidine (44mg, 0.34 mmol) were dissolved in isopropanol (20 ml). To this mixtureDiPEA (0.45 ml) was added and heated to 90° C. for 12 h. Isopropanol wasremoved on rotavapour to obtain a residue. Residue was purified bycombiflash using a gradient mixture of EtOAc and Petether (38:62) aseluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 220-222° C. MS (m/z): 471.2 [M+H]⁺

Example 82 Tert-butyl4-[2-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-5-yl]piperidine-1-carboxylate

Intermediate 52 (40 mg, 0.1 mmol),2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (30mg, 0.12 mmol) and KF (18 mg, 0.3 mmol) were dissolved in a mixture ofDMF (1 ml) and and water (0.4 ml). This mixture was purged with N₂ for30 mins. Pd(dppf)Cl₂.CH₂Cl₂ was added to the above mixture and againpurged with N₂ for 30 mins. This reaction mixture was heated to 90° C.for 12 h. Work up (EtOAc and H₂O) followed by purification on combiflashusing a gradient mixture of EtOAc and Petether (55:45) as eluentafforded the titled compound (3 mg) as an Off-White solid. MS (m/z):439.5 [M+H]⁺

Example 832-[2-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]benzo[d]oxazole

Intermediate 28 (150 mg, 0.41 mmol),3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride (96 mg,0.5 mmol), K₂CO₃ (59 mg, 0.43 mmol), CuCl (2 mg, 0.02 mmol), acetylacetone (5 mg, 0.05 mmol) were dissolved in NMP (1 ml). This reactionmixture was stirred at 130° C. for 16 h under N₂ atmposphere. Work up(EtOAc/H2O) followed by purification on combiflash using a gradientmixture of EtOAc and Petether (30:70) as eluent afforded the titledcompound (25 mg) as a pale-yellow solid. M. P.: 206-209° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.26 (d, J 8.2, 1H), 7.97 (d, J 1.4, 1H), 7.69 (d,J 1.4, 1H), 7.63 (dd, J 1.5, 8.2, 1H), 7.56-7.48 (m, 2H), 3.49-3.39 (m,2H), 3.15-3.04 (m, 5H), 3.03-2.93 (m, 2H), 2.25-2.16 (m, 4 h), 1.36 (d,J 7, 6H).

Example 84 Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate

Following the general procedure, tert-butyl4-[2-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(260 mg) was prepared from intermediate 55 (420 mg, 1.08 mmol) andtert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(358 mg, 1.08 mmol). tert-butyl4-[2-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(260 mg, 0.58 mmol) was dissolved in methanol (8 ml) and added Pd/C (5%)(520 mg). This mixture was stirred under H₂ pressure (6.5 kg) for 12 h.Combined methanol fractions were evaporated on rotavapour to obtain thecrude. Crude was purified on combiflash using a gradient mixture ofEtOAc and Petether (1:9) as eluent to afford the titled compound (150mg) as a white solid. M. P.: 174-179° C. MS (m/z): 446.46 [M+H]⁺.

Example 85 Isopropyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}piperazine-1-carboxylate

Intermediate 28 (490 mg, 1.32 mmol), N-Benzylpiprazine (280 mg, 1.6mmol), K₂CO₃ (190 mg, 1.4 mmol), CuCl (6.5 mg, 0.05 mmol), acetylacetone (17 mg, 0.12 mmol) were dissolved in NMP (2 ml). This reactionmixture was stirred at 130° C. for 15 h under N₂ atmposphere. Work up(EtOAc/H2O) followed by column purification on 60-120 mesh silica gelusing a gradient mixture of EtOAc and Petether (1:1) as eluent afforded5-(4-benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole(250 mg) as a yellow solid.5-(4-Benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole(130 mg, 0.28 mmol) dissolved in DCM (15 ml) and added isopropylchloroformate (102 mg, 0.84 mmol). This mixture was stirred at reflux for 18h. Work up (DCM/H₂O) followed by purification of the crude by columnchromatography on 230-400 mesh silica gel using a gradient mixture ofEtOAc and Petether (30:70) as eluent afforded the titled compound (25mg) as a pale-yellow solid. M.P.: 231-234° C. ¹H-NMR (δ ppm, CDCl₃, 400MHz): 8.28 (d, J 8.7, 1H), 7.96 (d, J 1.6, 1H), 7.68-7.64 (m, 2H),7.57-7.47 (m, 2H), 4.95 (septet, J 6.2, 1H), 3.71-3.63 (m, 4H),3.12-3.06 (m, 4H), 1.26 (d, J 6.2, 6H).

Example 86 Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate

Following the general procedure-1, the titled compound (230 mg) wasobtained from intermediate 58 (500 mg, 1.28 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(467 mg, 1.4 mmol) as an off-white solid. M.P.: 207-212° C. ¹H-NMR (δppm, CDCl₃, 400 MHz): 8.44-8.38 (m, 3H), 8.04 (d, J 2.2, 1H), 7.82 (d, J8.3, 2H), 6.13 (bs, 1H), 4.14 (d, J 2.6, 2H), 3.70 (t, J 5.6, 2H), 2.59(bs, 2H), 1.50 (s, 9H).

Example 87 Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}piperidine-1-carboxylate

Tert-butyl4-{2-[4-(trifluoromethyl)phenyl]oxazolo[5,4-b]pyridin-6-yl}-5,6-dihydropyridine-1(2H)-carboxylate(170 mg, 0.38 mmol) was dissolved in methanol (10 ml) and added Pd/C(5%) (283 mg). This mixture was stirred under H₂ pressure (6.5 kg) for12 h. Combined methanol fractions were evaporated on rotavapour toobtain the crude. Crude was purified on combiflash using a gradientmixture of EtOAc and Petether (1:9) as eluent to afford the titledcompound (35 mg) as a white solid. M. P.: 184-188° C. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.40 (d, J 8.1, 2H), 8.27 (d, J 2, 1H), 7.93 (d, J 2,1H), 7.81 (d, J 8.3, 2H), 4.31 (d, J 13.5, 2H), 2.91-2.81 (m, 3H), 1.91(d, J 12.9, 2H), 1.78-1.62 (m, 2H), 1.50 (s, 9H).

Biological Assay

The biological properties of the compounds of this invention may beconfirmed by a number of biological assays. The biological assays whichcan be been carried out with the compounds of the invention areexemplified below.

A. In Vitro Cyclic AMP Assay:

cAMP measurements were done using a Cisbio dynamic 2 HTRF kit (Cisbio,Bedford, Mass.) according to the manufacturer's protocol. Briefly,HEK293 cells (0.2×10⁶/well) were plated in a 24 well plate and incubatedovernight at 37° C. Cells were transfected with either empty vector DNAor human GPR119 expression plasmid DNA using Lipofectamine 2000(Invitrogen). After 24 h, transfected cells were harvested, counted andplated at 1000 cells/5 ul in a black 384 welled small volume plate.Cells were treated with desired concentrations of compounds andincubated for 60 min at room temperature. Lysis buffer containingcAMP-d2 and cryptate conjugate were added and incubated for 1 h. HRTFratio was measured on a microplate reader (BMG Labtech, Germany) at anexcitation wavelength of 337 nm and emission wavelengths of 665 and 620nm with an integration time of 400 μsec. Data were analyzed usingGraphpad Prism (Graphpad software; San Diego Calif.) for EC₅₀determination.

Results:

The results are as given in Table I as % Induction@ 10 tiM, Table II as% Induction@ 10 tiM and EC 50 in nM

B. In Vitro Mouse GPR 119 Cyclic AMP Assay:

cAMP measurements were done using a Cisbio dynamic 2 HTRF kit (Cisbio,Bedford, Mass.) according to the manufacturer's protocol. HEK293 Cellswere stably transfected with Mouse GPR119 expression plasmid DNA usingLipofectamine 2000 (Invitrogen) and maintained in culture. Cells wereharvested, counted and plated at 1000 cells/5 ul in a black 384 welledsmall volume plate. Cells were treated with desired concentrations ofcompounds and incubated for 60 min at room temperature. Lysis buffercontaining cAMP-d2 and cryptate conjugate were added and incubated for 1h. HRTF ratio was measured on a microplate reader (BMG Labtech, Germany)at an excitation wavelength of 337 nm and emission wavelengths of 665and 615 nm with an integration time of 400 μsec. Data were analyzedusing Graphpad Prism (Graphpad software; San Diego Calif.) for EC₅₀determination. For example example 12 showed an EC 50 of <25 nM

C. In Vitro HIT-T15 Cyclic AMP Assay:

cAMP measurements were done using a Cisbio dynamic 2 HTRF kit (Cisbio,Bedford, Mass.) according to the manufacturer's protocol. Briefly,HIT-T15 cells were harvested, counted and plated at 4000 cells/5 ulPBS-BSA solution in a black 384 welled small volume plate. Cells weretreated with desired concentrations of compounds and incubated for 60min at room temperature. Lysis buffer containing cAMP-d2 and cryptateconjugate were added and incubated for 1 h. HRTF ratio was measured on amicroplate reader (BMG Labtech, Germany) at an excitation wavelength of337 nm and emission wavelengths of 665 and 615 nm with an integrationtime of 400 μsec. Data were analyzed using Graphpad Prism (Graphpadsoftware; San Diego Calif.) for EC₅₀ determination. For instance example12 showed an EC 50 of <25 nM

D. In Vitro HIT-T15 Insulin Assay:

Insulin measurements were done using a Ultra Sensitive Insulin ELISA kit(Crystal Chem Inc, USA) according to the manufacturer's protocol.Briefly, 2.5×10⁵ HIT-15 cells/well were plated in 24 well plate andincubator for 24 hours. Next day, media was replaced with DMEM-3 mMGlucose with 10% Horse Serum, 2.5% FBS, 1% pen-strep and furtherincubated for 24 h. Cells were treated with desired concentrations ofcompounds and incubated for 60 min at room temperature. Supernatant wascollected, centrifuged and soup added to the pre-coated strips followedby ELISA. The absorbance was measured at 450 and 630 nM. Data wereanalyzed using Granhnad Prism (Granhnad software; San Diego Calif.) forEC₅₀ determination.

TABLE I COMPOUND Induction EC50* EXAMPLE-1 55.35 ND EXAMPLE-2 35.78 NDEXAMPLE-3 35.44 ND EXAMPLE-4 74.19 A EXAMPLE-5 40.98 ND EXAMPLE-6 73.22A+ EXAMPLE-7 62.63 A EXAMPLE-8 66.72 A+ EXAMPLE-9 46.83 ND EXAMPLE-1059.24 C EXAMPLE-11 70.09 ND EXAMPLE-12 82.95 A++ EXAMPLE-13 68.17 BEXAMPLE-14 68.59 A+ EXAMPLE-15 77.69 B EXAMPLE-16 43.71 ND EXAMPLE-1741.47 ND EXAMPLE-18 36.44 ND EXAMPLE-19 37.17 ND EXAMPLE-20 73.88 A+EXAMPLE-21 59.02 A EXAMPLE-22 64.55 ND EXAMPLE-23 69.56 A+ EXAMPLE-2467.48 A++ EXAMPLE-25 63.39 ND EXAMPLE-26 73.99 ND EXAMPLE-27 46.54 NDEXAMPLE-28 45.37 ND EXAMPLE-29 78.62 A+ EXAMPLE-30 62.20 C EXAMPLE-3180.38 A++ EXAMPLE-32 63.93 A EXAMPLE-33 10.61 ND EXAMPLE-34 — NDEXAMPLE-35 0.28 ND EXAMPLE-36 4.83 ND EXAMPLE-37 6.56 ND EXAMPLE-3816.59 ND EXAMPLE-39 27.49 ND EXAMPLE-40 21.87 ND EXAMPLE-41 — NDEXAMPLE-42 78.40 A+ EXAMPLE-43 48.77 ND EXAMPLE-44 64.79 A+ EXAMPLE-4556.43 ND EXAMPLE-46 53.02 ND EXAMPLE-47 33.13 ND EXAMPLE-48 26.66 NDEXAMPLE-49 32.86 ND EXAMPLE-50 38.68 ND EXAMPLE-51 38.73 ND EXAMPLE-5268.36 B EXAMPLE-53 39.87 ND ND: Not done; A++: ≦25 nM; A+: >25 to ≦50nM; A: >50 to ≦100 nM; B: >100 to ≦500 nM; C: >500 to ≦1000 nM; *Emaxvaries between 65 to 80%.

TABLE II COMPOUND Induction EC50* EXAMPLE-56 38.53 ND EXAMPLE-57 47.05ND EXAMPLE-58 32.25 ND EXAMPLE-59 63.76 ND EXAMPLE-60 72.78 A+EXAMPLE-61 29.77 ND EXAMPLE-62 59.34 B EXAMPLE-63 56.57 ND EXAMPLE-6475.03 A++ EXAMPLE-65 32.09 ND EXAMPLE-66 18.89 ND EXAMPLE-67 73.03 A+EXAMPLE-68 72.69 ND EXAMPLE-69 71.83 A+ EXAMPLE-70 64.66 A++ EXAMPLE-7176.63 A++ EXAMPLE-72 81.57 A++ EXAMPLE-73 46.02 C EXAMPLE-74 14.69 NDEXAMPLE-75 57.49 ND EXAMPLE-76 74.90 A EXAMPLE-77 80.37 A EXAMPLE-7859.36 ND EXAMPLE-79 46.17 ND EXAMPLE-80 26.39 ND EXAMPLE-81 42.96 NDEXAMPLE-82 ND ND EXAMPLE-83 57.64 ND EXAMPLE-84 13.17 ND EXAMPLE-85 NDND EXAMPLE-86 ND ND EXAMPLE-87 47.29 ND ND: Not done; ; A++: ≦25 nM;A+: >25 to ≦50 nM; A: >50 & <250 nM; B: <500 nM; C: >500 to ≦1000 nM;*Emax varies between 65 to 80%.

E: Oral Glucose Tolerance Test (OGTT) in C57Bl/6J Mice:

Results of the OGTT not only diagnose diabetes but can determine if asubject has impaired fasting glucose (IFG) or impaired glucose tolerance(IGT). Having either of these conditions indicates a significantlyincreased risk of developing diabetes in the future.

After the quarantine period, 6 hr fasted animals were randomized anddivided into various groups depending on their blood glucose levels.Test compounds or standard drug (sitagliptin) was prepared as asuspension in a vehicle consisting of 0.5% methylcellulose and Tween 80as a suspending agent. The standard drug, Compound A (example-64),Compound B (example-42) or vehicle were administered by oral gavage in avolume of 10 mL/kg. 1 h after the test compounds, standard drug andvehicle administration, blood was sampled from the tail vein of mice attime 0 min (baseline) and at 30, 60, 90 and 120 min after an oralglucose load of 2.0 g/kg of body weight. Food, but not water, waswithheld from the cages during the course of experiment. The area undercurve (AUC) of experimental animals was compared with that ofvehicle-treated control group. The results are shown in FIGS. 1 and 2and are discussed below.

Results:

Compound A and Sitagliptin dosed as single agents lowered AUC_(oucose)by 24% and 59%, respectively, and Compound B and sitagliptin dosed assingle agents lowered AUC_(oucose) by 22 and 50%, respectively.

F: Intraperitoneal Glucose Tolerance Test (IPGTT) in C57Bl/6J Mice:

After the quarantine period, 6 hr fasted animals are to be randomizedand divided into various groups depending on their blood glucose levels.Test compound or standard drug is to be prepared as a suspension in avehicle consisting of 0.5% methylcellulose in which Tween 80 as asuspending agent. The compound or vehicle is to be administered by oralgavage in a volume of 10 mL/kg. 1 h after drug or vehicleadministration, blood is to be sampled from the tail vein of mice attime 0 min (baseline) and at 30, 60, 90 and 120 min afterintraperitoneal administration of glucose solution of 2.0 g/kg of bodyweight. Food, but not water is to be withheld from the cages during thecourse of experiment. The area under curve (AUC) of experimental animalswill be compared with that of vehicle-treated control group.

G: Oral Glucose Tolerance Test (OGTT) in Streptozotocin & NicotinamideInduced Type 2 Diabetes in CD-1 Mice:

After the quarantine period, animals are to be randomized and dividedinto various groups depending on their body weights and animals are tobe administered with nicotinamide (100 mg/kg) and streptozotocin (150mg/kg) by intraperitoneally to induce diabetes. Sham control mice are tobe intraperitoneally administered with physiological saline. Two weekslater, the diabetic mice were grouped to provide similar meannon-fasting blood glucose levels in each group, 6 hr fasted animals areto be randomized and divided into various groups depending on theirblood glucose levels. Test compound or standard drug is to be preparedas a suspension in a vehicle consisting of 0.5% methylcellulose in whichTween 80 as a suspending agent. The compound or vehicle is to beadministered by oral gavage in a volume of 10 mL/kg. 1 h after drug orvehicle administration, blood is to be sampled from the tail vein ofmice at time 0 min (baseline) and at 30, 60, 90 and 120 min after anoral glucose load of 2.0 g/kg of body weight. Food, but not water is tobe withheld from the cages during the course of experiment. The areaunder curve (AUC) of experimental animals will be compared with that ofvehicle-treated control group.

H: Sub-Acute Treatment of Test Compound in Streptozotocin & NicotinamideInduced Type 2 Diabetes in CD-1 Mice:

After the quarantine period, animals are to be randomized and dividedinto various groups depending on their body weights and animals are tobe administered with nicotinamide (100 mg/kg) and streptozotocin (150mg/kg) by intraperitoneally to induce diabetes. Sham control mice are tobe intraperitoneally administered with physiological saline. Two weekslater, the diabetic mice are to be grouped to provide similar meannon-fasting blood glucose levels in each group, on day 0, fasted animalsare to be randomized and divided into various groups depending on theirblood glucose levels. Test compound or standard drug is to be preparedas a suspension in a vehicle consisting of 0.5% methylcellulose in whichTween 80 as a suspending agent. The compound or vehicle is to beadministered by oral gavage in a volume of 10 mL/kg. 1 h after drug orvehicle administration, blood is to be sampled from the tail vein ofmice at time 0 min (baseline) and at 30, 60, 90 and 120 min after anoral glucose load of 2.0 g/kg of body weight. Food, but not water is tobe withheld from the cages during the course of experiment. The areaunder curve (AUC) of experimental animals will be compared with that ofvehicle-treated control group. After conducting the OGTT on day 0, thetreatment will be continued for 14 days, on day 14, 6 hr fasted animalswill be used for the same OGTT procedure. After conducting the OGTT,blood samples will be collected from the animals and analysed for thelipid profile, insulin, and GLP-1 levels.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as described above.

All publications and patent and/or patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated herein by reference.

1-33. (canceled)
 34. A compound of formula (A-I), (A-II), (B-I), (B-II),(B-III) and (B-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxidethereof, wherein Ar is selected from substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl or Cy¹; X¹ is CR¹ or N; X² isCR² or N; X³ is CR³ or N; and X⁴ is CR⁴ or N; X is CR or N; Z is NR; Cy¹is selected from substituted or unsubstituted cycloalkyl or substitutedor unsubstituted heterocyclic group; each occurrence of R, R², and R³may be same or different and is independently selected from hydrogen,nitro, hydroxy, cyano, halogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substitutedor unsubstituted C₃₋₆ cycloalkylalkyl, substituted or unsubstituted C₃₋₆cycloalkenyl, —OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), C(═Y)—R^(a),—CR^(a)R^(b)—C(═Y)—R^(a), —CR^(a)R^(b)—Y—CR^(a)R^(b)—,—C(═Y)—NR^(a)R^(b)—, —NR^(a)—C(═Y)—NR^(a)R^(b)—,—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)—S(═O)_(q)—NR^(a)R^(b)—, and—NR^(a)—NR^(a)R^(b)—; each occurrence of R¹ and R⁴ may be same ordifferent and is independently selected from hydrogen, nitro, hydroxy,halogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₃₋₆ cycloalkylalkyl, substituted or unsubstituted C₃₋₆cycloalkenyl, —OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), C(═Y)—R^(a),—CR^(a)R^(b)—C(═Y)—R^(a), —CR^(a)R^(b)—Y—CR^(a)R^(b)—,—C(═Y)—NR^(a)R^(b)—, —NR^(a)—C(═Y)—NR^(a)R^(b)—,—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)—S(═O)_(q)—NR^(a)R^(b)—, and—NR^(a)—NR^(a)R^(b); each occurrence of R^(a) and R^(b) may be same ordifferent and are independently selected from hydrogen, nitro, hydroxy,cyano, halogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₃₋₆ cycloalkylalkyl, and substituted or unsubstitutedC₃₋₆ cycloalkenyl, or when two R^(a) and/or R^(b) substituents aredirectly bound to a common atom, they may be joined to form (i) an oxo(═O), thio (═S) or imino (═NR^(d)), or (ii) a substituted orunsubstituted, saturated or unsaturated 3-10 member ring, which mayoptionally include one or more heteroatoms which may be same ordifferent and are selected from O, NR^(c) or S; each occurrence of R^(c)is independently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl;each occurrence of Y is independently selected from O, S, and NR^(a);and each occurrence of q independently represents 0, 1 or 2; D and E areindependently selected from CH or N; R⁵ is selected from hydrogen,hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S),substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, —COOR^(a), —C(O)R^(a),—C(S)R^(a), —C(O)NR^(a)R^(b), —C(O)ONR^(a)R^(b), —NR^(a)R^(b),—NR^(a)CONR^(a)R^(b), —N(R^(a))SOR^(b), —N(R^(a))SO₂R^(b),-(═N—N(R^(a))R^(b)), —NR^(a)C(O)OR^(b), —NR^(a)C(O)R^(b)—,—NR^(a)C(S)R^(b) NR^(a)C(S)NR^(a)R^(b), —SONR^(a)R^(b)—, —OR^(a),—OR^(a)C(O)NR^(a)R^(b), —OR^(a)C(O)OR^(b)—, —OC(O)R^(a),—OC(O)NR^(a)R^(b), —R^(a)NR^(b)C(O)R^(a), —R^(a)OR^(b),—R^(a)C(O)OR^(b), —R^(a)C(O)NR^(a)R^(b), —R^(a)C(O)R^(b),—R^(a)OC(O)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a), and —ONO₂; with theproviso that when R⁵ is —SO₂R^(a), then R^(a) is not unsubstitutedalkyl; each occurrence of R^(d) is independently hydrogen, hydroxy,halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocycicyalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, and —ONO₂, or any two of R^(d) which aredirectly bound to a common atom may be joined to form (i) a substitutedor unsubstituted, saturated or unsaturated 3-14 membered ring, which mayoptionally include one or more heteroatoms which may be the same ordifferent and are selected from O, NR′ (where R′ is H or alkyl) or S, or(ii) an oxo (═O), thio (═S) or imino (═NR′); and each occurrence ofR^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k) and R^(l) isindependently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl; orany two of R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), and R^(l)may be joined to form (i) a substituted or unsubstituted, saturated orunsaturated 3-14 membered ring, which may optionally include one or moreheteroatoms which may be the same or different and are selected from O,NR′ (where R′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) orimino (═NR′) (where R′ is H or alkyl); and each of r, s, t and u is 0, 1or 2 with the proviso that r+s+t+u
 0. 35. A compound of formula (A-III)and (A-IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxidethereof, wherein Ar is selected from substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl or Cy¹; X¹ is CR¹ or N; X² isCR² or N; X³ is CR³ or N; and X⁴ is CR⁴ or N; X is CR or N; Z is NR; Cy¹is selected from substituted or unsubstituted cycloalkyl or substitutedor unsubstituted heterocyclic group; each occurrence of R, R², and R³may be same or different and is independently selected from hydrogen,nitro, hydroxy, cyano, halogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substitutedor unsubstituted C₃₋₆ cycloalkylalkyl, substituted or unsubstituted C₃₋₆cycloalkenyl, —OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), C(═Y)—R^(a),—CR^(a)R^(b)—C(═Y)—R^(a), —CR^(a)R^(b)—Y—CR^(a)R^(b)—,—C(═Y)—NR^(a)R^(b)—, —NR^(a)—C(═Y)—NR^(a)R^(b)—,—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)—S(═O)_(q)—NR^(a)R^(b)—, and—NR^(a)—NR^(a)R^(b)—; each occurrence of R¹ and R⁴ may be same ordifferent and is independently selected from hydrogen, nitro, hydroxy,halogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₃₋₆ cycloalkylalkyl, substituted or unsubstituted C₃₋₆cycloalkenyl, —OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), C(═Y)—R^(a),—CR^(a)R^(b)—C(═Y)—R^(a), —CR^(a)R^(b)—Y—CR^(a)R^(b)—,—C(═Y)—NR^(a)R^(b)—, —NR^(a)—C(═Y)—NR^(a)R^(b)—,—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)—S(═O)_(q)—NR^(a)R^(b)—, and—NR^(a)—NR^(a)R^(b)—; each occurrence of R^(a) and R^(b) may be same ordifferent and are independently selected from hydrogen, nitro, hydroxy,cyano, halogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₃₋₆ cycloalkylalkyl, and substituted or unsubstitutedC₃₋₆ cycloalkenyl, or when two R^(a) and/or R^(b) substituents aredirectly bound to a common atom, they may be joined to form (i) an oxo(═O), thio (═S) or imino (═NR^(d)), or (ii) a substituted orunsubstituted, saturated or unsaturated 3-10 member ring, which mayoptionally include one or more heteroatoms which may be same ordifferent and are selected from O, NR^(c) or S; each occurrence of R^(c)is independently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl;each occurrence of Y is independently selected from O, S, and NR^(a);and each occurrence of q independently represents 0, 1 or 2; D and E areindependently selected from CH or N; R⁵ is selected from hydrogen,hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S),substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, —COOR^(a), —C(O)R^(a),—C(S)R^(a), —C(O)NR^(a)R^(b), —C(O)ONR^(a)R^(b), —NR^(a)R^(b),—NR^(a)CONR^(a)R^(b), —N(R^(a))SOR^(b), —N(R^(a))SO₂R^(b),-(═N—N(R^(a))R^(b)), —NR^(a)C(O)OR^(b), —NR^(a)C(O)R^(b)—,—NR^(a)C(S)R^(b) NR^(a)C(S)NR^(a)R^(b), —SONR^(a)R^(b)—,—SO₂NR^(a)R^(b)—, —OR^(a), —OR^(a)C(O)NR^(a)R^(b), —OR^(a)C(O)OR^(b)—,—OC(O)R^(a), —OC(O)NR^(a)R^(b), —R^(a)NR^(b)C(O)R^(a), —R^(a)OR^(b),—R^(a)C(O)OR^(b), —R^(a)C(O)NR^(a)R^(b), —R^(a)C(O)R^(b),—R^(a)OC(O)R^(b), —SR^(a), —SOR^(a)—SO₂R^(a), and —ONO₂, each occurrenceof R^(d) is independently hydrogen, hydroxy, halogen, carboxyl, cyano,nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclcyalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, and —ONO₂, or any two of R^(d) which aredirectly bound to a common atom may be joined to form (i) a substitutedor unsubstituted, saturated or unsaturated 3-14 membered ring, which mayoptionally include one or more heteroatoms which may be the same ordifferent and are selected from O, NR′ (where R′ is H or alkyl) or S, or(ii) an oxo (═O), thio (═S) or imino (═NR′); and each occurrence ofR^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k) and R^(l) isindependently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl; orany two of R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), and R¹ maybe joined to form (i) a substituted or unsubstituted, saturated orunsaturated 3-14 membered ring, which may optionally include one or moreheteroatoms which may be the same or different and are selected from O,NR′ (where R′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) orimino (═NR′) (where R′ is H or alkyl); and each of r, s, t and u is 0, 1or 2 with the proviso that r+s+t+u≠0,
 36. A compound of claim 34,wherein Ar is selected from


37. A compound of claim 34, wherein Z is NH or N—CH₃.
 38. A compound ofclaim 34, wherein Cy¹ is selected from


39. A compound of claim 34, wherein R⁵ is selected from


40. A compound of claim 34, wherein R⁵ is —C(O)OC(CH₃)₃ or—C(O)OCH(CH₃)₂.
 41. A compound selected from2-[1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl]-5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole;Tert-butyl4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate;Tert-butyl4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate;Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate;Tert-butyl4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-5-yl}piperidine-1-carboxylate;5-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-2-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazole;and pharmaceutically acceptable salts thereof.
 42. A pharmaceuticalcomposition comprising a compound of claim 34 and a pharmaceuticallyacceptable carrier.
 43. The pharmaceutical composition of claim 34,further comprising one or more additional therapeutic agents andmixtures thereof.